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Henry A, Mo X, Finan C, Chaffin MD, Speed D, Issa H, Denaxas S, Ware JS, Zheng SL, Malarstig A, Gratton J, Bond I, Roselli C, Miller D, Chopade S, Schmidt AF, Abner E, Adams L, Andersson C, Aragam KG, Ärnlöv J, Asselin G, Raja AA, Backman JD, Bartz TM, Biddinger KJ, Biggs ML, Bloom HL, Boersma E, Brandimarto J, Brown MR, Brunak S, Bruun MT, Buckbinder L, Bundgaard H, Carey DJ, Chasman DI, Chen X, Cook JP, Czuba T, de Denus S, Dehghan A, Delgado GE, Doney AS, Dörr M, Dowsett J, Dudley SC, Engström G, Erikstrup C, Esko T, Farber-Eger EH, Felix SB, Finer S, Ford I, Ghanbari M, Ghasemi S, Ghouse J, Giedraitis V, Giulianini F, Gottdiener JS, Gross S, Guðbjartsson DF, Gui H, Gutmann R, Hägg S, Haggerty CM, Hedman ÅK, Helgadottir A, Hemingway H, Hillege H, Hyde CL, Aagaard Jensen B, Jukema JW, Kardys I, Karra R, Kavousi M, Kizer JR, Kleber ME, Køber L, Koekemoer A, Kuchenbaecker K, Lai YP, Lanfear D, Langenberg C, Lin H, Lind L, Lindgren CM, Liu PP, London B, Lowery BD, Luan J, Lubitz SA, Magnusson P, Margulies KB, Marston NA, Martin H, März W, Melander O, Mordi IR, Morley MP, Morris AP, Morrison AC, Morton L, Nagle MW, Nelson CP, Niessner A, Niiranen T, Noordam R, Nowak C, O'Donoghue ML, Ostrowski SR, Owens AT, Palmer CNA, Paré G, Pedersen OB, Perola M, Pigeyre M, Psaty BM, Rice KM, Ridker PM, Romaine SPR, Rotter JI, Ruff CT, Sabatine MS, Sallah N, Salomaa V, Sattar N, Shalaby AA, Shekhar A, Smelser DT, Smith NL, Sørensen E, Srinivasan S, Stefansson K, Sveinbjörnsson G, Svensson P, Tammesoo ML, Tardif JC, Teder-Laving M, Teumer A, Thorgeirsson G, Thorsteinsdottir U, Torp-Pedersen C, Tragante V, Trompet S, Uitterlinden AG, Ullum H, van der Harst P, van Heel D, van Setten J, van Vugt M, Veluchamy A, Verschuuren M, Verweij N, Vissing CR, Völker U, Voors AA, Wallentin L, Wang Y, Weeke PE, Wiggins KL, Williams LK, Yang Y, Yu B, Zannad F, Zheng C, Asselbergs FW, Cappola TP, Dubé MP, Dunn ME, Lang CC, Samani NJ, Shah S, Vasan RS, Smith JG, Holm H, Shah S, Ellinor PT, Hingorani AD, Wells Q, Lumbers RT. Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes. Nat Genet 2025; 57:815-828. [PMID: 40038546 DOI: 10.1038/s41588-024-02064-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 12/17/2024] [Indexed: 03/06/2025]
Abstract
Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.
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Affiliation(s)
- Albert Henry
- Institute of Cardiovascular Science, University College London, London, UK
- Institute of Health Informatics, University College London, London, UK
| | - Xiaodong Mo
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Chris Finan
- Institute of Cardiovascular Science, University College London, London, UK
| | - Mark D Chaffin
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Doug Speed
- Center for Quantitative Genetics and Genomics, Aarhus University, Aarhus, Denmark
| | - Hanane Issa
- Institute of Health Informatics, University College London, London, UK
| | - Spiros Denaxas
- Institute of Health Informatics, University College London, London, UK
- Health Data Research UK, London, UK
- British Heart Foundation Data Science Centre, London, UK
- The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, UK
| | - James S Ware
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- National Heart & Lung Institute, Imperial College London, London, UK
- MRC London Institute of Medical Sciences, Imperial College London, London, UK
- Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK
- Hammersmith Hospital, Imperial College Hospitals NHS Trust, London, UK
| | - Sean L Zheng
- National Heart & Lung Institute, Imperial College London, London, UK
- Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Anders Malarstig
- Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
- Pfizer Worldwide Research & Development, Cambridge, MA, USA
| | - Jasmine Gratton
- Institute of Cardiovascular Science, University College London, London, UK
| | - Isabelle Bond
- Institute of Cardiovascular Science, University College London, London, UK
| | - Carolina Roselli
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - David Miller
- Division of Biosciences, University College London, London, UK
| | - Sandesh Chopade
- Institute of Cardiovascular Science, University College London, London, UK
| | - A Floriaan Schmidt
- Institute of Cardiovascular Science, University College London, London, UK
- Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands
- Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Erik Abner
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | | | - Charlotte Andersson
- Department of Cardiology, Herlev Gentofte Hospital, Herlev, Denmark
- National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA
| | - Krishna G Aragam
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Johan Ärnlöv
- Department of Neurobiology, Care Sciences and Society/Section of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden
- School of Health and Social Sciences, Dalarna University, Falun, Sweden
| | | | - Anna Axelsson Raja
- Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Joshua D Backman
- Analytical Genetics, Regeneron Genetics Center, Tarrytown, NY, USA
| | - Traci M Bartz
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Kiran J Biddinger
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Mary L Biggs
- Department of Biostatistics, University of Washington, Seattle, WA, USA
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Heather L Bloom
- Department of Medicine, Division of Cardiology, Emory University Medical Center, Atlanta, GA, USA
| | - Eric Boersma
- Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Jeffrey Brandimarto
- Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Michael R Brown
- Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas School of Public Health, Houston, TX, USA
| | - Søren Brunak
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mie Topholm Bruun
- Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
| | | | - Henning Bundgaard
- Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - David J Carey
- Department of Molecular and Functional Genomics, Geisinger, Danville, PA, USA
| | - Daniel I Chasman
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Xing Chen
- Pfizer Worldwide Research & Development, Cambridge, MA, USA
| | - James P Cook
- Department of Biostatistics, University of Liverpool, Liverpool, UK
| | - Tomasz Czuba
- Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Simon de Denus
- Montreal Heart Institute, Montreal, Quebec, Canada
- Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada
| | - Abbas Dehghan
- MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, Imperial College London, London, UK
| | - Graciela E Delgado
- Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Alexander S Doney
- Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
| | - Marcus Dörr
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
| | - Joseph Dowsett
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Samuel C Dudley
- Department of Medicine, Cardiovascular Division, University of Minnesota, Minneapolis, MN, USA
| | - Gunnar Engström
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Christian Erikstrup
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
- Deparment of Clinical Medicine, Health, Aarhus University, Aarhus, Denmark
| | - Tõnu Esko
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Eric H Farber-Eger
- Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Stephan B Felix
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
| | - Sarah Finer
- Centre for Primary Care and Public Health, Wolfson Institute of Population Health, Queen Mary University of London, London, UK
| | - Ian Ford
- Robertson Center for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Mohsen Ghanbari
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Sahar Ghasemi
- DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
| | - Jonas Ghouse
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | | | - Franco Giulianini
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - John S Gottdiener
- Department of Medicine, Division of Cardiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Stefan Gross
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
| | - Daníel F Guðbjartsson
- deCODE genetics/Amgen Inc., Reykjavik, Iceland
- School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
| | - Hongsheng Gui
- Center for Individualized and Genomic Medicine Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Rebecca Gutmann
- Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Sara Hägg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | | | - Åsa K Hedman
- Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
| | | | - Harry Hemingway
- Institute of Health Informatics, University College London, London, UK
- Health Data Research UK, London, UK
| | - Hans Hillege
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Craig L Hyde
- Pfizer Worldwide Research & Development, Cambridge, MA, USA
| | | | - J Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands
| | - Isabella Kardys
- Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Ravi Karra
- Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC, USA
- Department of Pathology, Duke University Medical Center, Durham, NC, USA
| | - Maryam Kavousi
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Jorge R Kizer
- Cardiology Section, San Francisco Veterans Affairs Health System, and Departments of Medicine, Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
| | - Marcus E Kleber
- Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Lars Køber
- Department of Cardiology, Nordsjaellands Hospital, Copenhagen, Denmark
| | - Andrea Koekemoer
- Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Karoline Kuchenbaecker
- Division of Psychiatry, University College London, London, UK
- UCL Genetics Institute, University College London, London, UK
| | - Yi-Pin Lai
- Pfizer Worldwide Research & Development, Cambridge, MA, USA
| | - David Lanfear
- Center for Individualized and Genomic Medicine Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
- Heart and Vascular Institute, Henry Ford Hospital, Detroit, MI, USA
| | - Claudia Langenberg
- Precision Healthcare University Research Institute, Queen Mary University of London, London, UK
- Computational Medicine, Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Honghuang Lin
- National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Lars Lind
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Cecilia M Lindgren
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Peter P Liu
- University of Ottawa Heart Institute, Ottawa, Ontario, Canada
- Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Barry London
- Division of Cardiovascular Medicine and Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA, USA
| | - Brandon D Lowery
- Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jian'an Luan
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Steven A Lubitz
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Patrik Magnusson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Kenneth B Margulies
- Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Nicholas A Marston
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA
| | - Hilary Martin
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Winfried März
- Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Germany
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
- Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany
| | - Olle Melander
- Department of Internal Medicine, Clinical Sciences, Lund University and Skåne University Hospital, Malmö, Sweden
| | - Ify R Mordi
- Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
| | - Michael P Morley
- Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrew P Morris
- Department of Biostatistics, University of Liverpool, Liverpool, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Alanna C Morrison
- Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas School of Public Health, Houston, TX, USA
| | - Lori Morton
- Cardiovascular Research, Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | | | - Christopher P Nelson
- Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Alexander Niessner
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
| | - Teemu Niiranen
- Department of Medicine, Turku University Hospital and University of Turku, Turku, Finland
- National Institute for Health and Welfare, Helsinki, Finland
| | - Raymond Noordam
- Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Christoph Nowak
- Department of Neurobiology, Care Sciences and Society/Section of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden
| | - Michelle L O'Donoghue
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA
| | - Sisse Rye Ostrowski
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anjali T Owens
- Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Colin N A Palmer
- Division of Population Health and Genomics, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
| | - Guillaume Paré
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
- Population Health Research Institute, Hamilton, Ontario, Canada
| | - Ole Birger Pedersen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark
| | - Markus Perola
- National Institute for Health and Welfare, Helsinki, Finland
| | - Marie Pigeyre
- Population Health Research Institute, Hamilton, Ontario, Canada
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Bruce M Psaty
- Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA
- Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA
| | - Kenneth M Rice
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Paul M Ridker
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Simon P R Romaine
- Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Harbor-UCLA Medical Center, Torrance, CA, USA
- Departments of Pediatrics and Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA
- Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Christian T Ruff
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA
| | - Marc S Sabatine
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA
| | - Neneh Sallah
- Institute of Health Informatics, University College London, London, UK
| | - Veikko Salomaa
- National Institute for Health and Welfare, Helsinki, Finland
| | - Naveed Sattar
- BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Alaa A Shalaby
- Department of Medicine, Division of Cardiology, University of Pittsburgh Medical Center and VA Pittsburgh HCS, Pittsburgh, PA, USA
| | - Akshay Shekhar
- Cardiovascular Research, Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | - Diane T Smelser
- Department of Molecular and Functional Genomics, Geisinger, Danville, PA, USA
| | - Nicholas L Smith
- Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
- Department of Veterans Affairs Office of Research & Development, Seattle Epidemiologic Research and Information Center, Seattle, WA, USA
| | - Erik Sørensen
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Sundararajan Srinivasan
- Division of Population Health and Genomics, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
| | - Kari Stefansson
- deCODE genetics/Amgen Inc., Reykjavik, Iceland
- Department of Medicine, University of Iceland, Reykjavik, Iceland
| | | | - Per Svensson
- Department of Cardiology, Söderjukhuset, Stockholm, Sweden
- Department of Clinical Science and Education-Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Mari-Liis Tammesoo
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Jean-Claude Tardif
- Montreal Heart Institute, Montreal, Quebec, Canada
- Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Maris Teder-Laving
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Alexander Teumer
- DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Guðmundur Thorgeirsson
- deCODE genetics/Amgen Inc., Reykjavik, Iceland
- Department of Medicine, University of Iceland, Reykjavik, Iceland
- Department of Internal Medicine, Division of Cardiology, National University Hospital of Iceland, Reykjavik, Iceland
| | - Unnur Thorsteinsdottir
- deCODE genetics/Amgen Inc., Reykjavik, Iceland
- Department of Medicine, University of Iceland, Reykjavik, Iceland
| | | | | | - Stella Trompet
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
- Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Andre G Uitterlinden
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | | | - Pim van der Harst
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands
| | - David van Heel
- Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK
| | - Jessica van Setten
- Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Marion van Vugt
- Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Abirami Veluchamy
- Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
- Division of Population Health and Genomics, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
| | - Monique Verschuuren
- Department Life Course and Health, Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Niek Verweij
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Christoffer Rasmus Vissing
- Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Uwe Völker
- DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Adriaan A Voors
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Lars Wallentin
- Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
| | - Yunzhang Wang
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Peter E Weeke
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Kerri L Wiggins
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - L Keoki Williams
- Center for Individualized and Genomic Medicine Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Yifan Yang
- Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Bing Yu
- Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas School of Public Health, Houston, TX, USA
| | - Faiez Zannad
- Université de Lorraine, CHU de Nancy, Inserm and INI-CRCT (F-CRIN), Institut Lorrain du Coeur et des Vaisseaux, Vandoeuvre Lès Nancy, France
| | - Chaoqun Zheng
- Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Folkert W Asselbergs
- Institute of Health Informatics, University College London, London, UK
- The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, UK
- Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Thomas P Cappola
- Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marie-Pierre Dubé
- Montreal Heart Institute, Montreal, Quebec, Canada
- Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Michael E Dunn
- Cardiovascular Research, Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | - Chim C Lang
- Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
| | - Nilesh J Samani
- Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Svati Shah
- Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC, USA
- Duke Clinical Research Institute, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
| | - Ramachandran S Vasan
- National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA
- Sections of Cardiology, Preventive Medicine and Epidemiology, Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, MA, USA
| | - J Gustav Smith
- Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University and Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden
- Wallenberg Center for Molecular Medicine and Lund University Diabetes Center, Lund University, Lund, Sweden
| | - Hilma Holm
- deCODE genetics/Amgen Inc., Reykjavik, Iceland
| | - Sonia Shah
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Patrick T Ellinor
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Cambridge, MA, USA
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Aroon D Hingorani
- Institute of Cardiovascular Science, University College London, London, UK
| | - Quinn Wells
- Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN, USA
| | - R Thomas Lumbers
- Institute of Health Informatics, University College London, London, UK.
- Health Data Research UK, London, UK.
- The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, UK.
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2
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Lee D, Gunamalai L, Kannan J, Vickery K, Yaacov O, Onuchic-Whitford AC, Chakravarti A, Kapoor A. Massively parallel reporter assays identify functional enhancer variants at QT interval GWAS loci. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.11.642686. [PMID: 40161821 PMCID: PMC11952420 DOI: 10.1101/2025.03.11.642686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Genome-wide association studies (GWAS) have identified >30 loci with multiple common noncoding variants explaining interindividual electrocardiographic QT interval (QTi) variation. Of the many types of noncoding functional elements, here we sought to identify transcriptional enhancers with sequence variation and their cognate transcription factors (TFs) that alter the expression of proximal cardiac genes to affect QTi variation. We used massively parallel reporter assays (MPRA) in mouse cardiomyocyte HL-1 cells to screen for functional enhancer variants among 1,018 QTi-associated GWAS variants that overlap candidate cardiac enhancers across 31 loci. We identified 445 GWAS variant-containing enhancers of which 79 showed significant allelic difference in enhancer activity across 21 GWAS loci, with multiple enhancer variants per locus. Of these, we predicted differential binding by cardiac TFs, including AP-1, ATF-1, GATA2, MEF2, NKX2.5, SRF and TBX5 which are known to play key roles in development and homeostasis, at 49 enhancer variants. Finally, we used expression quantitative trait locus mapping and predicted promoter-enhancer contacts to identify 14 candidate target genes through analyses of 36 enhancer variants at 16 loci. This study provides strong evidence for 14 cardiac genes, 10 of them novel, impacting on QTi variation, beyond explaining observed genetic associations.
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Affiliation(s)
- Dongwon Lee
- Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute, Cambridge, MA, USA
| | - Lavanya Gunamalai
- Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jeerthi Kannan
- Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Boston, MA, USA
- Broad Institute, Cambridge, MA, USA
| | - Kyla Vickery
- Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Or Yaacov
- Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, NY, USA
| | - Ana C. Onuchic-Whitford
- Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute, Cambridge, MA, USA
- Renal division, Brigham and Women’s Hospital, Boston, MA, USA
| | - Aravinda Chakravarti
- Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, NY, USA
| | - Ashish Kapoor
- Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
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3
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Arora A, Zareba W, Woosley RL, Klimentidis YC, Patel IY, Quan SF, Wendel C, Shamoun F, Guerra S, Parthasarathy S, Patel SI. Genetic QT score as a predictor of sudden cardiac death in participants with sleep-disordered breathing in the UK Biobank. J Clin Sleep Med 2025; 21:549-557. [PMID: 39589075 PMCID: PMC11874099 DOI: 10.5664/jcsm.11474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 11/27/2024]
Abstract
STUDY OBJECTIVES The goal of this study was to evaluate the association between a polygenic risk score (PRS) for QT prolongation (QTc-PRS), corrected QT intervals (QTc) and sudden cardiac death (SCD) in participants enrolled in the UK Biobank with and without sleep-disordered breathing (SDB). METHODS The QTc-PRS was calculated using allele copy number and previously reported effect estimates for each single nuclear polymorphism. Competing-risk regression models adjusting for age, sex, body mass index, QT prolonging medication, race, and comorbid cardiovascular conditions were used for SCD analyses. RESULTS A total of 500,584 participants were evaluated (56.5 ± 8 years, 54% female, 1.4% diagnosed with sleep apnea). A higher QTc-PRS was independently associated with the increased QTc interval duration (P < .0001). The mean QTc for the top QTc-PRS quintile was 15 msec longer than the bottom quintile (P < .001). SDB was found to be an effect modifier in the relationship between QTc-PRS and SCD. The adjusted hazard ratio per 5-unit change in QTc-PRS for SCD was 1.64 (95% confidence interval 1.16-2.31, P = .005) among those with SDB and 1.04 (95% confidence interval 0.95-1.14, P = .44) among those without SDB (P for interaction = .01). Black participants with SDB had significantly elevated adjusted risk of SCD (hazard ratio = 9.6, 95% confidence interval 1.24-74, P = .03). CONCLUSIONS In the UK Biobank population, the QTc-PRS was associated with SCD among participants with SDB but not among those without SDB, indicating that SDB is a significant modifier of the genetic risk. Black participants with SDB had a particularly high risk of SCD. CITATION Arora A, Zareba W, Woosley RL, et al. Genetic QT score as a predictor of sudden cardiac death in participants with sleep-disordered breathing in the UK Biobank. J Clin Sleep Med. 2025;21(3):549-557.
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Affiliation(s)
- Amit Arora
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona
| | - Wojciech Zareba
- Division of Cardiology, University of Rochester Medical Center, Rochester, New York
| | - Raymond L. Woosley
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona
| | - Yann C. Klimentidis
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona
| | - Imran Y. Patel
- El Rio Health, Tucson, Arizona
- UAHS Center for Sleep and Circadian Sciences, University of Arizona, Tucson, Arizona
- Division of Pulmonary, Allergy, Critical Care Medicine and Sleep Medicine, University of Arizona College of Medicine – Tucson, Tucson, Arizona
| | - Stuart F. Quan
- UAHS Center for Sleep and Circadian Sciences, University of Arizona, Tucson, Arizona
- Division of Pulmonary, Allergy, Critical Care Medicine and Sleep Medicine, University of Arizona College of Medicine – Tucson, Tucson, Arizona
| | - Christopher Wendel
- UAHS Center for Sleep and Circadian Sciences, University of Arizona, Tucson, Arizona
| | | | - Stefano Guerra
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona
- Division of Pulmonary, Allergy, Critical Care Medicine and Sleep Medicine, University of Arizona College of Medicine – Tucson, Tucson, Arizona
- Asthma and Airway Disease Research Center, University of Arizona, Tucson, Arizona
| | - Sairam Parthasarathy
- UAHS Center for Sleep and Circadian Sciences, University of Arizona, Tucson, Arizona
- Division of Pulmonary, Allergy, Critical Care Medicine and Sleep Medicine, University of Arizona College of Medicine – Tucson, Tucson, Arizona
| | - Salma I. Patel
- UAHS Center for Sleep and Circadian Sciences, University of Arizona, Tucson, Arizona
- Division of Pulmonary, Allergy, Critical Care Medicine and Sleep Medicine, University of Arizona College of Medicine – Tucson, Tucson, Arizona
- The University of Arizona College of Health Sciences, Tucson, Arizona
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4
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Zhang X, Procopio SB, Ding H, Semel MG, Schroder EA, Viggars MR, Seward TS, Du P, Wu K, Johnson SR, Prabhat A, Schneider DJ, Stumpf IG, Rozmus ER, Huo Z, Delisle BP, Esser KA. The Core Circadian Clock Factor, Bmal1, Transduces Sex-specific Differences in Both Rhythmic and Nonrhythmic Gene Expression in the Mouse Heart. FUNCTION 2025; 6:zqae053. [PMID: 39658371 PMCID: PMC11815582 DOI: 10.1093/function/zqae053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/25/2024] [Accepted: 12/02/2024] [Indexed: 12/12/2024] Open
Abstract
It has been well established that cardiovascular diseases exhibit significant differences between sexes in both preclinical models and humans. In addition, there is growing recognition that disrupted circadian rhythms can contribute to the onset and progression of cardiovascular diseases. However, little is known about sex differences between the cardiac circadian clock and circadian transcriptomes in mice. Here, we show that the core clock genes are expressed in common in both sexes, but the cardiac circadian transcriptome is very sex-specific. Hearts from female mice expressed significantly more rhythmically expressed genes (REGs) than male hearts, and the temporal distribution of REGs was distinctly different between sexes. To test the contribution of the circadian clock in sex-specific gene expression in the heart, we knocked out the core circadian clock factor Bmal1 in adult cardiomyocytes. The sex differences in the circadian transcriptomes were significantly diminished with cardiomyocyte-specific loss of Bmal1. Surprisingly, loss of cardiomyocyte Bmal1 also resulted in a roughly 8-fold reduction in the number of all differentially expressed genes between male and female hearts. We highlight sex-specific changes in several cardiac-specific transcription factors, including Gata4, Nkx2-5, and Tbx5. While there is still much to learn, we conclude that cardiomyocyte-specific Bmal1 is vital in conferring sex-specific gene expression in the adult mouse heart.
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Affiliation(s)
- Xiping Zhang
- Department of Physiology and Aging, University of Florida, Gainesville, FL 32610, USA
| | - Spencer B Procopio
- Department of Physiology and Aging, University of Florida, Gainesville, FL 32610, USA
| | - Haocheng Ding
- Department of Biostatics, University of Florida, Gainesville, FL 32611, USA
| | - Maya G Semel
- Department of Physiology and Aging, University of Florida, Gainesville, FL 32610, USA
| | - Elizabeth A Schroder
- Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
- Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Mark R Viggars
- Department of Physiology and Aging, University of Florida, Gainesville, FL 32610, USA
| | - Tanya S Seward
- Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
| | - Ping Du
- Department of Physiology and Aging, University of Florida, Gainesville, FL 32610, USA
| | - Kevin Wu
- Department of Physiology and Aging, University of Florida, Gainesville, FL 32610, USA
| | - Sidney R Johnson
- Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
| | - Abhilash Prabhat
- Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
| | - David J Schneider
- Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
| | - Isabel G Stumpf
- Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
| | - Ezekiel R Rozmus
- Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
| | - Zhiguang Huo
- Department of Biostatics, University of Florida, Gainesville, FL 32611, USA
| | - Brian P Delisle
- Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
| | - Karyn A Esser
- Department of Physiology and Aging, University of Florida, Gainesville, FL 32610, USA
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5
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Lopez-Medina AI, Campos-Staffico AM, Chahal CAA, Jacoby JP, Volkers I, Berenfeld O, Luzum JA. Polygenic risk score for drug-induced long QT syndrome: independent validation in a real-world patient cohort. Pharmacogenet Genomics 2025; 35:45-56. [PMID: 39470415 PMCID: PMC11543509 DOI: 10.1097/fpc.0000000000000548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/30/2024]
Abstract
OBJECTIVE Drug-induced long QT syndrome (diLQTS) is an adverse reaction from over 150 FDA-approved medications, posing the risk of triggering torsades de pointes and sudden death. While common genetic variants may modestly impact QT interval individually, their collective effect can significantly amplify risk of diLQTS. Consequently, this study aimed to validate a polygenic risk score (PRS) for diLQTS previously proposed by Strauss et al . METHODS A retrospective cohort study was conducted utilizing patients from the Michigan Genomics Initiative prescribed 27 high-risk QT-prolonging drugs and an ECG during the prescription. The primary outcome was marked prolongation of the QTc interval (either >60 ms change from baseline or >500 ms absolute value) during treatment with a high-risk QT-prolonging drug. RESULTS The primary outcome occurred in 12.0% of n = 6070 self-reported White, 12.4% of 558 African American, and 8.2% of 110 Asian patients. The PRS significantly associated with diLQTS in White patients [adjusted odds ratio = 1.44 (95% CI: 1.09-1.89); P = 0.009]. However the study lacked sufficient statistical power to confirm the PRS as a risk factor in African Americans [adjusted odds ratio = 2.18 (95% CI: 0.98-5.49); P = 0.073] and Asians [adjusted odds ratio = 3.21 (95% CI: 0.69-16.87); P = 0.139] due to smaller sample sizes in these groups. CONCLUSION The previously published PRS for diLQTS was validated in a large, real-world cohort, demonstrating its potential as a tool for identifying high-risk patients. Incorporating this PRS into routine clinical practice could enable proactive measures to prevent life-threatening diLQTS.
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Affiliation(s)
- Ana I Lopez-Medina
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, United States
| | | | - Choudhary Anwar A Chahal
- Center for Inherited Cardiovascular Diseases, WellSpan Health, Lancaster, PA, USA. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA. Department of Cardiology, Barts Heart Centre, London, UK, Queen Mary University of London, London, UK
| | - Juliet P. Jacoby
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, United States
| | - Isabella Volkers
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, United States
| | - Omer Berenfeld
- Center for Arrhythmia Research, Departments of Internal Medicine – Cardiology, Biomedical Engineering, and Applied Physics. University of Michigan, Ann Arbor, MI, United States
| | - Jasmine A. Luzum
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, United States
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6
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Weng LC, Rämö JT, Jurgens SJ, Khurshid S, Chaffin M, Hall AW, Morrill VN, Wang X, Nauffal V, Sun YV, Beer D, Lee S, Nadkarni GN, Duong T, Wang B, Czuba T, Austin TR, Yoneda ZT, Friedman DJ, Clayton A, Hyman MC, Judy RL, Skanes AC, Orland KM, Treu TM, Oetjens MT, Alonso A, Soliman EZ, Lin H, Lunetta KL, van der Pals J, Issa TZ, Nafissi NA, May HT, Leong-Sit P, Roselli C, Choi SH, Khan HR, Knight S, Karlsson Linnér R, Bezzina CR, Ripatti S, Heckbert SR, Gaziano JM, Loos RJF, Psaty BM, Smith JG, Benjamin EJ, Arking DE, Rader DJ, Shah SH, Roden DM, Damrauer SM, Eckhardt LL, Roberts JD, Cutler MJ, Shoemaker MB, Haggerty CM, Cho K, Palotie A, Wilson PWF, Ellinor PT, Lubitz SA. The impact of common and rare genetic variants on bradyarrhythmia development. Nat Genet 2025; 57:53-64. [PMID: 39747593 PMCID: PMC11735381 DOI: 10.1038/s41588-024-01978-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 10/09/2024] [Indexed: 01/04/2025]
Abstract
To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (rg = 0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias.
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Grants
- R01 HL141901 NHLBI NIH HHS
- R01 HL139738 NHLBI NIH HHS
- 18SFRN34250007 American Heart Association (American Heart Association, Inc.)
- TNE FANTASY 19CV03 Fondation Leducq
- R01 HL092577 NHLBI NIH HHS
- R01 HL105756 NHLBI NIH HHS
- R01 HL157635 NHLBI NIH HHS
- R01 HL139731 NHLBI NIH HHS
- U01 AG068221 NIA NIH HHS
- 23CDA1050571 American Heart Association (American Heart Association, Inc.)
- T32 HL007101 NHLBI NIH HHS
- R01 AG083735 NIA NIH HHS
- 18SFRN34110082 American Heart Association (American Heart Association, Inc.)
- 18SFRN34230127 American Heart Association (American Heart Association, Inc.)
- IK2 CX001780 CSRD VA
- 75N92019D00031 NHLBI NIH HHS
- K23 HL169839 NHLBI NIH HHS
- 03-007-2022-0035 Hartstichting (Dutch Heart Foundation)
- R21 HL175584 NHLBI NIH HHS
- R01 HL163987 NHLBI NIH HHS
- National Institutes of Health:R01HL139731 & R01HL157635
- Sigrid Juséliuksen Säätiö (Sigrid Jusélius Foundation)
- National Institutes of Health: K23HL169839
- National Institutes of Health: RO1HL092577
- National Institutes of Health: T32HL007101
- Swedish Heart-Lung Foundation (2022-0344, 2022-0345), the Swedish Research Council (2021-02273), the European Research Council (ERC-STG-2015-679242), Gothenburg University, Skane University Hospital, the Scania county, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and Swedish Foundation for Strategic Research (Dnr IRC15-0067) to the Lund University Diabetes Center.
- US Department of Veterans Affairs Clinical Research and Development award IK2-CX001780
- National Institutes of Health: R01HL163987-01 and R01HL139738-01
- Academy of Finland Centre of Excellence in Complex Disease Genetics (grant no. 312074 and 336824)
- National Institutes of Health: R01HL139731, R01HL157635, and RO1HL092577 European Union: MAESTRIA 965286
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Affiliation(s)
- Lu-Chen Weng
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- VA Boston Healthcare System, Boston, MA, USA
| | - Joel T Rämö
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Sean J Jurgens
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Shaan Khurshid
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Telemachus and Irene Demoulas Family Foundation Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA
| | - Mark Chaffin
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Amelia Weber Hall
- Gene Regulation Observatory, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Valerie N Morrill
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Xin Wang
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Victor Nauffal
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- VA Boston Healthcare System, Boston, MA, USA
- Cardiovascular Medicine Division, Brigham and Women's Hospital, Boston, MA, USA
| | - Yan V Sun
- VA Atlanta Healthcare System, Decatur, GA, USA
- Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA
| | | | - Simon Lee
- Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | | | - ThuyVy Duong
- McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Biqi Wang
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Tomasz Czuba
- The Wallenberg Laboratory/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University, Gothenburg, Sweden
- Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Thomas R Austin
- Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Zachary T Yoneda
- Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Daniel J Friedman
- Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Anne Clayton
- Intermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA
| | - Matthew C Hyman
- Division of Cardiac Electrophysiology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Renae L Judy
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Allan C Skanes
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada
| | - Kate M Orland
- Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | | | - Matthew T Oetjens
- Autism and Developmental Medicine Institute, Geisinger, Lewisburg, PA, USA
| | - Alvaro Alonso
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Elsayed Z Soliman
- Epidemiological Cardiology Research Center, Section on Cardiovascular Medicine, Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Honghuang Lin
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Kathryn L Lunetta
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Jesper van der Pals
- Department of Cardiology, Clinical Sciences, Lund University and Skane University Hospital, Lund, Sweden
| | - Tariq Z Issa
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Navid A Nafissi
- Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Heidi T May
- Intermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA
| | - Peter Leong-Sit
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada
| | - Carolina Roselli
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Seung Hoan Choi
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Habib R Khan
- Section of Cardiac Electrophysiology, Western University, London, Ontario, Canada
| | - Stacey Knight
- Intermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA
- Department of Medicine, University of Utah, Salt Lake City, UT, USA
| | - Richard Karlsson Linnér
- Autism and Developmental Medicine Institute, Geisinger, Lewisburg, PA, USA
- Department of Economics, Leiden Law School, Leiden University, Leiden, The Netherlands
| | - Connie R Bezzina
- Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Center, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Samuli Ripatti
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Susan R Heckbert
- Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - J Michael Gaziano
- VA Boston Healthcare System, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Ruth J F Loos
- Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
- Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bruce M Psaty
- Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA
- Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA
| | - J Gustav Smith
- The Wallenberg Laboratory/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University, Gothenburg, Sweden
- Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Cardiology, Clinical Sciences, Lund University and Skane University Hospital, Lund, Sweden
- Wallenberg Center for Molecular Medicine and Lund University Diabetes Center, Lund University, Lund, Sweden
| | - Emelia J Benjamin
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
- Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
- NHLBI and BU's Framingham Heart Study, Framingham, MA, USA
| | - Dan E Arking
- McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daniel J Rader
- Departments of Medicine and Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Svati H Shah
- Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA
| | - Dan M Roden
- Vanderbilt University Medical Center, Nashville, TN, USA
| | - Scott M Damrauer
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Lee L Eckhardt
- Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Jason D Roberts
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada
| | - Michael J Cutler
- Intermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA
| | - M Benjamin Shoemaker
- Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Christopher M Haggerty
- Heart Institute, Geisinger, Danville, PA, USA
- Department of Translational Data Science and Informatics, Geisinger, Danville, PA, USA
| | - Kelly Cho
- VA Boston Healthcare System, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Aarno Palotie
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
- The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
| | - Peter W F Wilson
- VA Atlanta Healthcare System, Decatur, GA, USA
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Patrick T Ellinor
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Telemachus and Irene Demoulas Family Foundation Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA
| | - Steven A Lubitz
- Telemachus and Irene Demoulas Family Foundation Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA.
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7
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Bukaeva A, Ershova A, Kharlap M, Kiseleva A, Kutsenko V, Sotnikova E, Divashuk M, Pokrovskaya M, Garbuzova E, Blokhina A, Kopylova O, Zotova E, Petukhova A, Zharikova A, Ramensky V, Zaicenoka M, Vyatkin Y, Meshkov A, Drapkina O. The Yield of Genetic Testing and Putative Genetic Factors of Disease Heterogeneity in Long QT Syndrome Patients. Int J Mol Sci 2024; 25:11976. [PMID: 39596046 PMCID: PMC11593843 DOI: 10.3390/ijms252211976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/02/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
Genetic overdiagnosis of long QT syndrome (LQTS) becomes a critical concern due to the high clinical significance of DNA diagnosis. Current guidelines for LQTS genetic testing recommend a limited scope and strict referral based on the Schwartz score. Nevertheless, LQTS may be underdiagnosed in patients with borderline phenotypes. We aimed to evaluate the total yield of rare variants in cardiac genes in LQTS patients. The cohort of 82 patients with LQTS referral diagnosis underwent phenotyping, Schwartz score counting, and exome sequencing. We assessed known LQTS genes for diagnostics, as per guidelines, and a broader set of genes for research. Diagnostic testing yield reached 75% in index patients; all causal variants were found in KCNQ1, KCNH2, and SCN5A genes. Research testing of 248 heart-related genes achieved a 50% yield of molecular diagnosis in patients with a low Schwartz score (<3.5). In patients with LQTS-causing variants, each additional rare variant in heart-related genes added 0.94 points to the Schwartz score (p value = 0.04), reflecting the more severe disease in such patients than in those with causal variants but without additional findings. We conclude that the current LQTS genetic diagnosis framework is highly specific but may lack sensitivity for patients with a Schwartz score <3.5. Improving referral criteria for these patients could enhance DNA diagnosis. Also, our results suggest that additional variants in cardiac genes may affect the severity of the disease in the carriers of LQTS-causing variants, which may aid in identifying new modifier genes.
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Affiliation(s)
- Anna Bukaeva
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
| | - Alexandra Ershova
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
| | - Maria Kharlap
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
| | - Anna Kiseleva
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
| | - Vladimir Kutsenko
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
| | - Evgeniia Sotnikova
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
| | - Mikhail Divashuk
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
- All-Russia Research Institute of Agricultural Biotechnology, 127550 Moscow, Russia
| | - Maria Pokrovskaya
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
| | - Elizaveta Garbuzova
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
| | - Anastasia Blokhina
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
| | - Oksana Kopylova
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
| | - Evgenia Zotova
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
| | - Anna Petukhova
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
| | - Anastasia Zharikova
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Vasily Ramensky
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia
- MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Marija Zaicenoka
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
- Moscow Center for Advanced Studies, 123592 Moscow, Russia
| | - Yuri Vyatkin
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
- MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Alexey Meshkov
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
| | - Oxana Drapkina
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.E.); (M.K.); (A.K.); (V.K.); (M.D.); (M.P.); (E.G.); (A.B.); (A.P.); (A.Z.); (V.R.); (M.Z.); (Y.V.); (A.M.); (O.D.)
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8
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Camara MD, Zhou Y, Dara A, Tékété MM, Nóbrega de Sousa T, Sissoko S, Dembélé L, Ouologuem N, Hamidou Togo A, Alhousseini ML, Fofana B, Sagara I, Djimde AA, Gil PJ, Lauschke VM. Population-specific variations in KCNH2 predispose patients to delayed ventricular repolarization upon dihydroartemisinin-piperaquine therapy. Antimicrob Agents Chemother 2024; 68:e0139023. [PMID: 38546223 PMCID: PMC11064487 DOI: 10.1128/aac.01390-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 03/05/2024] [Indexed: 05/03/2024] Open
Abstract
Dihydroartemisinin-piperaquine is efficacious for the treatment of uncomplicated malaria and its use is increasing globally. Despite the positive results in fighting malaria, inhibition of the Kv11.1 channel (hERG; encoded by the KCNH2 gene) by piperaquine has raised concerns about cardiac safety. Whether genetic factors could modulate the risk of piperaquine-mediated QT prolongations remained unclear. Here, we first profiled the genetic landscape of KCNH2 variability using data from 141,614 individuals. Overall, we found 1,007 exonic variants distributed over the entire gene body, 555 of which were missense. By optimizing the gene-specific parametrization of 16 partly orthogonal computational algorithms, we developed a KCNH2-specific ensemble classifier that identified a total of 116 putatively deleterious missense variations. To evaluate the clinical relevance of KCNH2 variability, we then sequenced 293 Malian patients with uncomplicated malaria and identified 13 variations within the voltage sensing and pore domains of Kv11.1 that directly interact with channel blockers. Cross-referencing of genetic and electrocardiographic data before and after piperaquine exposure revealed that carriers of two common variants, rs1805121 and rs41314375, experienced significantly higher QT prolongations (ΔQTc of 41.8 ms and 61 ms, respectively, vs 14.4 ms in controls) with more than 50% of carriers having increases in QTc >30 ms. Furthermore, we identified three carriers of rare population-specific variations who experienced clinically relevant delayed ventricular repolarization. Combined, our results map population-scale genetic variability of KCNH2 and identify genetic biomarkers for piperaquine-induced QT prolongation that could help to flag at-risk patients and optimize efficacy and adherence to antimalarial therapy.
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Affiliation(s)
- Mahamadou D. Camara
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali
| | - Yitian Zhou
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Antoine Dara
- Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali
| | - Mamadou M. Tékété
- Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali
| | - Taís Nóbrega de Sousa
- Department of Microbiology and Tumour Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Molecular Biology and Malaria Immunology Research Group, Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, Brazil
| | - Sékou Sissoko
- Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali
| | - Laurent Dembélé
- Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali
| | - Nouhoun Ouologuem
- Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali
| | - Amadou Hamidou Togo
- Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali
| | - Mohamed L. Alhousseini
- Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali
| | - Bakary Fofana
- Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali
| | - Issaka Sagara
- Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali
| | - Abdoulaye A. Djimde
- Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali
| | - Pedro J. Gil
- Department of Microbiology and Tumour Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Global Health and Tropical Medicine, Institute of Hygiene and Tropical Medicine, Nova University of Lisbon, Lisbon, Portugal
| | - Volker M. Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
- University of Tübingen, Tübingen, Germany
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9
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Kadagandla S, Kapoor A. Identification of candidate causal cis -regulatory variants underlying electrocardiographic QT interval GWAS loci. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.13.584880. [PMID: 38585875 PMCID: PMC10996567 DOI: 10.1101/2024.03.13.584880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Identifying causal variants among tens or hundreds of associated variants at each locus mapped by genome-wide association studies (GWAS) of complex traits is a challenge. As vast majority of GWAS variants are noncoding, sequence variation at cis -regulatory elements affecting transcriptional expression of specific genes is a widely accepted molecular hypothesis. Following this cis -regulatory hypothesis and combining it with the observation that nucleosome-free open chromatin is a universal hallmark of all types of cis -regulatory elements, we aimed to identify candidate causal regulatory variants underlying electrocardiographic QT interval GWAS loci. At a dozen loci, selected for higher effect sizes and a better understanding of the likely causal gene, we identified and included all common variants in high linkage disequilibrium with the GWAS variants as candidate variants. Using ENCODE DNase-seq and ATAC-seq from multiple human adult cardiac left ventricle tissue samples, we generated genome-wide maps of open chromatin regions marking putative regulatory elements. QT interval associated candidate variants were filtered for overlap with cardiac left ventricle open chromatin regions to identify candidate causal cis -regulatory variants, which were further assessed for colocalizing with a known cardiac GTEx expression quantitative trait locus variant as additional evidence for their causal role. Together, these efforts have generated a comprehensive set of candidate causal variants that are expected to be enriched for cis -regulatory potential and thereby, explaining the observed genetic associations.
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10
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Busonero F, Lenarduzzi S, Crobu F, Gentile RM, Carta A, Cracco F, Maschio A, Camarda S, Marongiu M, Zanetti D, Conversano C, Di Lorenzo G, Mazzà D, De Seta F, Girotto G, Sanna S. The Women4Health cohort: a unique cohort to study women-specific mechanisms of cardio-metabolic regulation. EUROPEAN HEART JOURNAL OPEN 2024; 4:oeae012. [PMID: 38532851 PMCID: PMC10964981 DOI: 10.1093/ehjopen/oeae012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/22/2024] [Accepted: 02/26/2024] [Indexed: 03/28/2024]
Abstract
Aims Epidemiological research has shown relevant differences between sexes in clinical manifestations, severity, and progression of cardiovascular and metabolic disorders. To date, the mechanisms underlying these differences remain unknown. Given the rising incidence of such diseases, gender-specific research on established and emerging risk factors, such as dysfunction of glycaemic and/or lipid metabolism, of sex hormones and of gut microbiome, is of paramount importance. The relationships between sex hormones, gut microbiome, and host glycaemic and/or lipid metabolism are largely unknown even in the homoeostasis status. Yet this knowledge gap would be pivotal to pinpoint to key mechanisms that are likely to be disrupted in disease context. Methods and results Here we present the Women4Health (W4H) cohort, a unique cohort comprising up to 300 healthy women followed up during a natural menstrual cycle, set up with the primary goal to investigate the combined role of sex hormones and gut microbiota variations in regulating host lipid and glucose metabolism during homoeostasis, using a multi-omics strategy. Additionally, the W4H cohort will take into consideration another ecosystem that is unique to women, the vaginal microbiome, investigating its interaction with gut microbiome and exploring-for the first time-its role in cardiometabolic disorders. Conclusion The W4H cohort study lays a foundation for improving current knowledge of women-specific mechanisms in cardiometabolic regulation. It aspires to transform insights on host-microbiota interactions into prevention and therapeutic approaches for personalized health care.
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Affiliation(s)
- Fabio Busonero
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
| | - Stefania Lenarduzzi
- Institute for Maternal and Child Health—IRCCS ‘Burlo Garofolo’, Via dell'Istria 65/1, Trieste, 34137, TS, Italy
| | - Francesca Crobu
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
| | - Roberta Marie Gentile
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, Trieste, 34137, TS, Italy
| | - Andrea Carta
- Department of Business and Economics, University of Cagliari, via Università 40, 09124, Cagliari, CA, Italy
| | - Francesco Cracco
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, Trieste, 34137, TS, Italy
| | - Andrea Maschio
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
| | - Silvia Camarda
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, Trieste, 34137, TS, Italy
| | - Michele Marongiu
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
| | - Daniela Zanetti
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
| | - Claudio Conversano
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
- Department of Business and Economics, University of Cagliari, via Università 40, 09124, Cagliari, CA, Italy
| | - Giovanni Di Lorenzo
- Institute for Maternal and Child Health—IRCCS ‘Burlo Garofolo’, Via dell'Istria 65/1, Trieste, 34137, TS, Italy
| | - Daniela Mazzà
- Institute for Maternal and Child Health—IRCCS ‘Burlo Garofolo’, Via dell'Istria 65/1, Trieste, 34137, TS, Italy
| | - Francesco De Seta
- Institute for Maternal and Child Health—IRCCS ‘Burlo Garofolo’, Via dell'Istria 65/1, Trieste, 34137, TS, Italy
| | - Giorgia Girotto
- Institute for Maternal and Child Health—IRCCS ‘Burlo Garofolo’, Via dell'Istria 65/1, Trieste, 34137, TS, Italy
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, Trieste, 34137, TS, Italy
| | - Serena Sanna
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
- Department of Genetics, University Medical Center Groningen, Hanzeplein 1, 97123 GZ, Groningen, The Netherlands
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11
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Schulze-Bahr E. [Cardiogenetics in Germany- a view and review]. Herzschrittmacherther Elektrophysiol 2024; 35:127-137. [PMID: 38418599 PMCID: PMC10924006 DOI: 10.1007/s00399-024-01008-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2024] [Indexed: 03/01/2024]
Abstract
The development of the cardiogenetics field in Germany has been increasing since the mid-1990s with many national contributions, some of them were really important and groundbreaking. The starting point was and still is the patient and his family, e.g. with a familial form of arrhythmia or cardiomyopathy, the clarification of the genetic cause and the personalized treatment of those being affected. The scientific, always translationally oriented interest in identifying a causative gene and uncovering the underlying pathomechanisms has led to notable contributions for Brugada syndrome, short QT syndrome and cardiac conduction disorders or sinus node dysfunction, but also in DCM or ARVC. What is important, however, is always the way back (bench > bed side): implementation of national and international recommendations for cardiogenetic diagnostics in daily cardiological routine and the personalized care and therapy of those being affected.
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Affiliation(s)
- E Schulze-Bahr
- Institut für Genetik von Herzerkrankungen (IfGH), Spezialambulanz für Patienten mit genetischen Herzerkrankungen, Universitätsklinikum Münster (UKM), Domagkstr. 3, 48145, Münster, Deutschland.
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12
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Kabakov AY, Roder K, Bronk P, Turan NN, Dhakal S, Zhong M, Lu Y, Zeltzer ZA, Najman-Licht YB, Karma A, Koren G. E3 ubiquitin ligase rififylin has yin and yang effects on rabbit cardiac transient outward potassium currents (I to) and corresponding channel proteins. J Biol Chem 2024; 300:105759. [PMID: 38367666 PMCID: PMC10945274 DOI: 10.1016/j.jbc.2024.105759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 01/23/2024] [Accepted: 02/09/2024] [Indexed: 02/19/2024] Open
Abstract
Genome-wide association studies have reported a correlation between a SNP of the RING finger E3 ubiquitin protein ligase rififylin (RFFL) and QT interval variability in humans (Newton-Cheh et al., 2009). Previously, we have shown that RFFL downregulates expression and function of the human-like ether-a-go-go-related gene potassium channel and corresponding rapidly activating delayed rectifier potassium current (IKr) in adult rabbit ventricular cardiomyocytes. Here, we report that RFFL also affects the transient outward current (Ito), but in a peculiar way. RFFL overexpression in adult rabbit ventricular cardiomyocytes significantly decreases the contribution of its fast component (Ito,f) from 35% to 21% and increases the contribution of its slow component (Ito,s) from 65% to 79%. Since Ito,f in rabbits is mainly conducted by Kv4.3, we investigated the effect of RFFL on Kv4.3 expressed in HEK293A cells. We found that RFFL overexpression reduced Kv4.3 expression and corresponding Ito,f in a RING domain-dependent manner in the presence or absence of its accessory subunit Kv channel-interacting protein 2. On the other hand, RFFL overexpression in Kv1.4-expressing HEK cells leads to an increase in both Kv1.4 expression level and Ito,s, similarly in a RING domain-dependent manner. Our physiologically detailed rabbit ventricular myocyte computational model shows that these yin and yang effects of RFFL overexpression on Ito,f, and Ito,s affect phase 1 of the action potential waveform and slightly decrease its duration in addition to suppressing IKr. Thus, RFFL modifies cardiac repolarization reserve via ubiquitination of multiple proteins that differently affect various potassium channels and cardiac action potential duration.
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Affiliation(s)
- Anatoli Y Kabakov
- Division of Cardiology, Department of Medicine, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Karim Roder
- Division of Cardiology, Department of Medicine, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Peter Bronk
- Division of Cardiology, Department of Medicine, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Nilüfer N Turan
- Division of Cardiology, Department of Medicine, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Saroj Dhakal
- Physics Department and Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, Massachusetts, USA
| | - Mingwang Zhong
- Physics Department and Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, Massachusetts, USA
| | - Yichun Lu
- Division of Cardiology, Department of Medicine, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Zachary A Zeltzer
- Division of Cardiology, Department of Medicine, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Yonatan B Najman-Licht
- Division of Cardiology, Department of Medicine, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Alain Karma
- Physics Department and Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, Massachusetts, USA
| | - Gideon Koren
- Division of Cardiology, Department of Medicine, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.
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13
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Zhang M, Hillegass WB, Yu X, Majumdar S, Daryl Pollard J, Jackson E, Knudson J, Wolfe D, Kato GJ, Maher JF, Mei H. Genetic variants and effect modifiers of QT interval prolongation in patients with sickle cell disease. Gene 2024; 890:147824. [PMID: 37741592 DOI: 10.1016/j.gene.2023.147824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/17/2023] [Accepted: 09/20/2023] [Indexed: 09/25/2023]
Abstract
BACKGROUND Sickle cell disease (SCD) is a common inherited blood disorder among African Americans (AA), with premature mortality which has been associated with prolongation of the heart rate-corrected QT interval (QTc), a known risk factor for sudden cardiac death. Although numerous genetic variants have been identified as contributors to QT interval prolongation in the general population, their impact on SCD patients remains unclear. This study used an unweighted polygenic risk score (PRS) to validate the previously identified associations between SNPs and QTc interval in SCD patients, and to explore possible interactions with other factors that prolong QTc interval in AA individuals with SCD. METHODS In SCD patients, candidate genetic variants associated with the QTc interval were genotyped. To identify any risk SNPs that may be correlated with QTc interval prolongation, linear regression was employed, and an unweighted PRS was subsequently constructed. The effect of PRS on the QTc interval was evaluated using linear regression, while stratification analysis was used to assess the influence of serum alanine transaminase (ALT), a biomarker for liver disease, on the PRS effect. We also evaluated the PRS with the two subcomponents of QTc, the QRS and JTc intervals. RESULTS Out of 26 candidate SNPs, five risk SNPs were identified for QTc duration under the recessive model. For every unit increase in PRS, the QTc interval prolonged by 4.0 ms (95% CI: [2.0, 6.1]; p-value: <0.001) in the additive model and 9.4 ms in the recessive model (95% CI: [4.6, 14.1]; p-value: <0.001). Serum ALT showed a modification effect on PRS-QTc prolongation under the recessive model. In the normal ALT group, each PRS unit increased QTc interval by 11.7 ms (95% CI: [6.3, 17.1]; p-value: 2.60E-5), whereas this effect was not observed in the elevated ALT group (0.9 ms; 95% CI: [-7.0, 8.8]; p-value: 0.823). CONCLUSION Several candidate genetic variants are associated with QTc interval prolongation in SCD patients, and serum ALT acts as a modifying factor. The association of a CPS1 gene variant in both QTc and JTc duration adds to NOS1AP as evidence of involvement of the urea cycle and nitric oxide metabolism in cardiac repolarization in SCD. Larger replication studies are needed to confirm these findings and elucidate the underlying mechanisms.
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Affiliation(s)
- Mengna Zhang
- Department of Data Science, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - William B Hillegass
- Department of Data Science, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Xue Yu
- Department of Data Science, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Suvankar Majumdar
- Division of Hematology, Children's National Hospital, Washington, DC, USA
| | - J Daryl Pollard
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Erin Jackson
- Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Jarrod Knudson
- Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Douglas Wolfe
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Gregory J Kato
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Joseph F Maher
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Internal Medicine/Cancer Genetics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.
| | - Hao Mei
- Department of Data Science, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
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14
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Arora A, Zareba W, Woosley RL, Klimentidis YC, Patel IY, Quan SF, Wendel C, Shamoun F, Guerra S, Parthasarathy S, Patel SI. Genetic QT Score and Sleep Apnea as Predictors of Sudden Cardiac Death in the UK Biobank. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.11.07.23298237. [PMID: 37986981 PMCID: PMC10659512 DOI: 10.1101/2023.11.07.23298237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
Introduction The goal of this study was to evaluate the association between a polygenic risk score (PRS) for QT prolongation (QTc-PRS), QTc intervals and mortality in patients enrolled in the UK Biobank with and without sleep apnea. Methods The QTc-PRS was calculated using allele copy number and previously reported effect estimates for each single nuclear polymorphism SNP. Competing-risk regression models adjusting for age, sex, BMI, QT prolonging medication, race, and comorbid cardiovascular conditions were used for sudden cardiac death (SCD) analyses. Results 500,584 participants were evaluated (56.5 ±8 years, 54% women, 1.4% diagnosed with sleep apnea). A higher QTc-PRS was independently associated with the increased QTc interval duration (p<0.0001). The mean QTc for the top QTc-PRS quintile was 15 msec longer than the bottom quintile (p<0.001). Sleep apnea was found to be an effect modifier in the relationship between QTc-PRS and SCD. The adjusted HR per 5-unit change in QTc-PRS for SCD was 1.64 (95% CI 1.16 - 2.31, p=0.005) among those with sleep apnea and 1.04 (95% CI 0.95 - 1.14, p=0.44) among those without sleep apnea (p for interaction =0.01). Black participants with sleep apnea had significantly elevated adjusted risk of SCD compared to White participants (HR=9.6, 95% CI 1.24 - 74, p=0.03). Conclusion In the UK Biobank population, the QTc-PRS was associated with SCD among participants with sleep apnea but not among those without sleep apnea, indicating that sleep apnea is a significant modifier of the genetic risk. Black participants with sleep apnea had a particularly high risk of SCD.
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15
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Jonmundsson T, Steindorsdottir AE, Austin TR, Frick EA, Axelsson GT, Launer L, Psaty BM, Loureiro J, Orth AP, Aspelund T, Emilsson V, Floyd JS, Jennings L, Gudnason V, Gudmundsdottir V. A proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study). Europace 2023; 25:euad320. [PMID: 37967346 PMCID: PMC10685397 DOI: 10.1093/europace/euad320] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/01/2023] [Accepted: 10/06/2023] [Indexed: 11/17/2023] Open
Abstract
AIMS Atrial fibrillation (AF) is associated with high risk of comorbidities and mortality. Our aim was to examine causal and predictive relationships between 4137 serum proteins and incident AF in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study. METHODS AND RESULTS The study included 4765 participants, of whom 1172 developed AF. Cox proportional hazards regression models were fitted for 4137 baseline protein measurements adjusting for known risk factors. Protein associations were tested for replication in the Cardiovascular Health Study (CHS). Causal relationships were examined in a bidirectional, two-sample Mendelian randomization analysis. The time-dependent area under the receiver operating characteristic curve (AUC)-statistic was examined as protein levels and an AF-polygenic risk score (PRS) were added to clinical risk models. The proteomic signature of incident AF consisted of 76 proteins, of which 63 (83%) were novel and 29 (38%) were replicated in CHS. The signature included both N-terminal prohormone of brain natriuretic peptide (NT-proBNP)-dependent (e.g. CHST15, ATP1B1, and SVEP1) and independent components (e.g. ASPN, AKR1B, and LAMA1/LAMB1/LAMC1). Nine causal candidates were identified (TAGLN, WARS, CHST15, CHMP3, COL15A1, DUSP13, MANBA, QSOX2, and SRL). The reverse causal analysis suggested that most AF-associated proteins were affected by the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide improved the prediction of incident AF events close to baseline with further improvements gained by the AF-PRS at all time points. CONCLUSION The AF proteomic signature includes biologically relevant proteins, some of which may be causal. It mainly reflects an NT-proBNP-dependent consequence of the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide is a promising marker for incident AF in the short term, but risk assessment incorporating a PRS may improve long-term risk assessment.
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Affiliation(s)
- Thorarinn Jonmundsson
- Icelandic Heart Association, Holtasmari 1, Kopavogur 201, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
| | | | - Thomas R Austin
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Elisabet A Frick
- Icelandic Heart Association, Holtasmari 1, Kopavogur 201, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
| | - Gisli T Axelsson
- Icelandic Heart Association, Holtasmari 1, Kopavogur 201, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
| | - Lenore Launer
- Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA
| | - Bruce M Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
- Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA
| | | | | | - Thor Aspelund
- Icelandic Heart Association, Holtasmari 1, Kopavogur 201, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
| | - Valur Emilsson
- Icelandic Heart Association, Holtasmari 1, Kopavogur 201, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
| | - James S Floyd
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | | | - Vilmundur Gudnason
- Icelandic Heart Association, Holtasmari 1, Kopavogur 201, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
| | - Valborg Gudmundsdottir
- Icelandic Heart Association, Holtasmari 1, Kopavogur 201, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
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16
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Smith A, Auer D, Johnson M, Sanchez E, Ross H, Ward C, Chakravarti A, Kapoor A. Cardiac muscle-restricted partial loss of Nos1ap expression has limited but significant impact on electrocardiographic features. G3 (BETHESDA, MD.) 2023; 13:jkad208. [PMID: 37708408 PMCID: PMC10627271 DOI: 10.1093/g3journal/jkad208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 08/16/2023] [Accepted: 09/06/2023] [Indexed: 09/16/2023]
Abstract
Genome-wide association studies have identified sequence polymorphisms in a functional enhancer of the NOS1AP gene as the most common genetic regulator of QT interval and human cardiac NOS1AP gene expression in the general population. Functional studies based on in vitro overexpression in murine cardiomyocytes and ex vivo knockdown in zebrafish embryonic hearts, by us and others, have also demonstrated that NOS1AP expression levels can alter cellular electrophysiology. Here, to explore the role of NOS1AP in cardiac electrophysiology at an organismal level, we generated and characterized constitutive and heart muscle-restricted Nos1ap knockout mice to assess whether NOS1AP disruption alters the QT interval in vivo. Constitutive loss of Nos1ap led to genetic background-dependent variable lethality at or right before birth. Heart muscle-restricted Nos1ap knockout, generated using cardiac-specific alpha-myosin heavy chain promoter-driven tamoxifen-inducible Cre, resulted in tissue-level Nos1ap expression reduced by half. This partial loss of expression had no detectable effect on the QT interval or other electrocardiographic and echocardiographic parameters, except for a small but significant reduction in the QRS interval. Given that challenges associated with defining the end of the T wave on murine electrocardiogram can limit identification of subtle effects on the QT interval and that common noncoding NOS1AP variants are also associated with the QRS interval, our findings support the role of NOS1AP in regulation of the cardiac electrical cycle.
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Affiliation(s)
- Alexa Smith
- Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Dallas Auer
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Morgan Johnson
- Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Ernesto Sanchez
- Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Holly Ross
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Christopher Ward
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Aravinda Chakravarti
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Center for Human Genetics and Genomics, New York University School of Medicine, New York, NY 10016, USA
| | - Ashish Kapoor
- Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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17
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Niskanen JE, Ohlsson Å, Ljungvall I, Drögemüller M, Ernst RF, Dooijes D, van Deutekom HWM, van Tintelen JP, Snijders Blok CJB, van Vugt M, van Setten J, Asselbergs FW, Petrič AD, Salonen M, Hundi S, Hörtenhuber M, Kere J, Pyle WG, Donner J, Postma AV, Leeb T, Andersson G, Hytönen MK, Häggström J, Wiberg M, Friederich J, Eberhard J, Harakalova M, van Steenbeek FG, Wess G, Lohi H. Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human. Genome Med 2023; 15:73. [PMID: 37723491 PMCID: PMC10506233 DOI: 10.1186/s13073-023-01221-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 08/17/2023] [Indexed: 09/20/2023] Open
Abstract
BACKGROUND Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis. METHODS We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts. RESULTS Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes. CONCLUSIONS Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies.
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Affiliation(s)
- Julia E Niskanen
- Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland
- Department of Veterinary Biosciences, University of Helsinki, Agnes Sjöbergin katu 2, 00790, Helsinki, Finland
- Folkhälsan Research Center, Haartmaninkatu 8, P.O.Box 63, 00290, Helsinki, Finland
| | - Åsa Ohlsson
- Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Ingrid Ljungvall
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Michaela Drögemüller
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, 3001, Switzerland
| | - Robert F Ernst
- Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Dennis Dooijes
- Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Hanneke W M van Deutekom
- Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
| | - J Peter van Tintelen
- Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Christian J B Snijders Blok
- Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
- Regenerative Medicine Centre Utrecht, University of Utrecht, Utrecht, The Netherlands
| | - Marion van Vugt
- Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
| | - Jessica van Setten
- Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
| | - Folkert W Asselbergs
- Amsterdam University Medical Centers, Department of Cardiology, University of Amsterdam, Amsterdam, The Netherlands
- Health Data Research UK and Institute of Health Informatics, University College London, London, UK
| | | | - Milla Salonen
- Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland
- Department of Veterinary Biosciences, University of Helsinki, Agnes Sjöbergin katu 2, 00790, Helsinki, Finland
- Folkhälsan Research Center, Haartmaninkatu 8, P.O.Box 63, 00290, Helsinki, Finland
| | - Sruthi Hundi
- Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland
- Department of Veterinary Biosciences, University of Helsinki, Agnes Sjöbergin katu 2, 00790, Helsinki, Finland
- Folkhälsan Research Center, Haartmaninkatu 8, P.O.Box 63, 00290, Helsinki, Finland
| | - Matthias Hörtenhuber
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - Juha Kere
- Folkhälsan Research Center, Haartmaninkatu 8, P.O.Box 63, 00290, Helsinki, Finland
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
- Research Programs Unit, Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, Finland
| | - W Glen Pyle
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada
- IMPART Investigator Team Canada, Dalhousie Medicine, Saint John, NB, Canada
| | - Jonas Donner
- Wisdom Panel Research Team, Wisdom Panel, Kinship, Helsinki, Finland
| | - Alex V Postma
- Department of Human Genetics, Amsterdam University Medical Center, Amsterdam, The Netherlands
- Department of Medical Biology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Tosso Leeb
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, 3001, Switzerland
| | - Göran Andersson
- Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Marjo K Hytönen
- Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland
- Department of Veterinary Biosciences, University of Helsinki, Agnes Sjöbergin katu 2, 00790, Helsinki, Finland
- Folkhälsan Research Center, Haartmaninkatu 8, P.O.Box 63, 00290, Helsinki, Finland
| | - Jens Häggström
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Maria Wiberg
- Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland
| | - Jana Friederich
- LMU Small Animal Clinic, Ludwig Maximilians University of Munich, Munich, Germany
| | - Jenny Eberhard
- LMU Small Animal Clinic, Ludwig Maximilians University of Munich, Munich, Germany
| | - Magdalena Harakalova
- Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
- Regenerative Medicine Centre Utrecht, University of Utrecht, Utrecht, The Netherlands
| | - Frank G van Steenbeek
- Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
- Regenerative Medicine Centre Utrecht, University of Utrecht, Utrecht, The Netherlands
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, Utrecht, 3584 CM, The Netherlands
| | - Gerhard Wess
- LMU Small Animal Clinic, Ludwig Maximilians University of Munich, Munich, Germany
| | - Hannes Lohi
- Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.
- Department of Veterinary Biosciences, University of Helsinki, Agnes Sjöbergin katu 2, 00790, Helsinki, Finland.
- Folkhälsan Research Center, Haartmaninkatu 8, P.O.Box 63, 00290, Helsinki, Finland.
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18
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Yuan L, Bu S, Du M, Wang Y, Ju C, Huang D, Xu W, Tan X, Liang M, Deng S, Yang L, Huang K. RNF207 exacerbates pathological cardiac hypertrophy via post-translational modification of TAB1. Cardiovasc Res 2023; 119:183-194. [PMID: 35352799 DOI: 10.1093/cvr/cvac039] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 02/14/2022] [Accepted: 03/14/2022] [Indexed: 11/14/2022] Open
Abstract
AIMS The heart undergoes pathological remodelling, featured by the hypertrophic growth of cardiomyocytes and increased cardiac fibrosis, under biomechanical stress such as haemodynamic overload. Ring Finger Protein 207 (RNF207) is an E3 ubiquitin ligase that is predominantly expressed in the heart, but its function remains elusive. In this study, we aimed to explore the role of RNF207 in the development of pathological cardiac hypertrophy and dysfunction. METHODS AND RESULTS Transverse aortic constriction (TAC) surgery was performed on mice to induce cardiac hypertrophy. Cardiac function and remodelling were evaluated by echocardiography, histological assessment, and molecular analyses. Our data indicated that RNF207 overexpression (OE) exacerbated cardiac hypertrophy, fibrosis, and systolic dysfunction. In contrast, TAC-induced cardiac remodelling was profoundly blunted in RNF207 knockdown (KD) hearts. In line with the in vivo findings, RNF207 OE augmented, whereas RNF207 KD alleviated, phenylephrine-induced cardiomyocyte hypertrophy in vitro. Mechanistically, we demonstrated that RNF207 elicited detrimental effects by promoting K63-linked ubiquitination of TAK1-binding protein 1 (TAB1), which triggered the autophosphorylation of transforming growth factor-β activated kinase 1 (TAK1) and the activation of downstream p38 and c-Jun N-terminal kinase (JNK)1/2 signalling pathways. In the TAB1-KD cardiomyocytes, RNF207-OE-induced cell hypertrophy was significantly attenuated, indicating that RNF207-induced hypertrophy is, at least in part, TAB1-dependent. CONCLUSIONS This study demonstrates that RNF207 exacerbates pressure overload-induced cardiac hypertrophy and dysfunction via post-translational modification of TAB1.
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Affiliation(s)
- Lin Yuan
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, Hubei, China
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong, China
| | - Shichen Bu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, Hubei, China
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Meng Du
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, Hubei, China
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Yilong Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, Hubei, China
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Chenhui Ju
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, Hubei, China
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Dandan Huang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, Hubei, China
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Wenjing Xu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, Hubei, China
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Xin Tan
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Minglu Liang
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Shan Deng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, Hubei, China
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Liu Yang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, Hubei, China
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Kai Huang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, Hubei, China
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Huazhong University of Science and Technology, Wuhan, Hubei, China
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19
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Vaiman EE, Shnayder NA, Zhuravlev NM, Petrova MM, Asadullin AR, Al-Zamil M, Garganeeva NP, Shipulin GA, Cumming P, Nasyrova RF. Genetic Biomarkers of Antipsychotic-Induced Prolongation of the QT Interval in Patients with Schizophrenia. Int J Mol Sci 2022; 23:ijms232415786. [PMID: 36555428 PMCID: PMC9785058 DOI: 10.3390/ijms232415786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/07/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Antipsychotics (AP) induced prolongation of the QT interval in patients with schizophrenia (Sch) is an actual interdisciplinary problem as it increases the risk of sudden death syndrome. Long QT syndrome (LQTS) as a cardiac adverse drug reaction is a multifactorial symptomatic disorder, the development of which is influenced by modifying factors (APs' dose, duration of APs therapy, APs polytherapy, and monotherapy, etc.) and non-modifying factors (genetic predisposition, gender, age, etc.). The genetic predisposition to AP-induced LQTS may be due to several causes, including causal mutations in the genes responsible for monoheme forms of LQTS, single nucleotide variants (SNVs) of the candidate genes encoding voltage-dependent ion channels expressed both in the brain and in the heart, and SNVs of candidate genes encoding key enzymes of APs metabolism. This narrative review summarizes the results of genetic studies on AP-induced LQTS and proposes a new personalized approach to assessing the risk of its development (low, moderate, high). We recommend implementation in protocols of primary diagnosis of AP-induced LQTS and medication dispensary additional observations of the risk category of patients receiving APs, deoxyribonucleic acid profiling, regular electrocardiogram monitoring, and regular therapeutic drug monitoring of the blood APs levels.
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Affiliation(s)
- Elena E. Vaiman
- Institute of Personalized Psychiatry and Neurology, V. M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
| | - Natalia A. Shnayder
- Institute of Personalized Psychiatry and Neurology, V. M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- Shared Core Facilities “Molecular and Cell Technologies”, V. F. Voyno-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia
- Correspondence: (N.A.S.); (R.F.N.); Tel.: +7-(812)-670-02-20 (N.A.S. & R.F.N.)
| | - Nikita M. Zhuravlev
- Institute of Personalized Psychiatry and Neurology, V. M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
| | - Marina M. Petrova
- Shared Core Facilities “Molecular and Cell Technologies”, V. F. Voyno-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia
| | - Azat R. Asadullin
- Department of Psychiatry and Addiction, Bashkir State Medical University, 450008 Ufa, Russia
| | - Mustafa Al-Zamil
- Department of Physiotherapy, Faculty of Continuing Medical Education, Peoples’ Friendship University of Russia, 117198 Moscow, Russia
| | - Natalia P. Garganeeva
- Department of General Medical Practice and Outpatient Therapy, Siberian State Medical University, 634050 Tomsk, Russia
| | - German A. Shipulin
- Centre for Strategic Planning and Management of Biomedical Health Risks Management, 119121 Moscow, Russia
| | - Paul Cumming
- Department of Nuclear Medicine, Bern University Hospital, 3010 Bern, Switzerland
- School of Psychology and Counselling, Queensland University of Technology, Brisbane 4000, Australia
| | - Regina F. Nasyrova
- Institute of Personalized Psychiatry and Neurology, V. M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- International Centre for Education and Research in Neuropsychiatry, Samara State Medical University, 443016 Samara, Russia
- Correspondence: (N.A.S.); (R.F.N.); Tel.: +7-(812)-670-02-20 (N.A.S. & R.F.N.)
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20
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Hoffmann TJ, Lu M, Oni-Orisan A, Lee C, Risch N, Iribarren C. A large genome-wide association study of QT interval length utilizing electronic health records. Genetics 2022; 222:iyac157. [PMID: 36271874 PMCID: PMC9713425 DOI: 10.1093/genetics/iyac157] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 09/22/2022] [Indexed: 12/13/2022] Open
Abstract
QT interval length is an important risk factor for adverse cardiovascular outcomes; however, the genetic architecture of QT interval remains incompletely understood. We conducted a genome-wide association study of 76,995 ancestrally diverse Kaiser Permanente Northern California members enrolled in the Genetic Epidemiology Research on Adult Health and Aging cohort using 448,517 longitudinal QT interval measurements, uncovering 9 novel variants, most replicating in 40,537 individuals in the UK Biobank and Population Architecture using Genomics and Epidemiology studies. A meta-analysis of all 3 cohorts (n = 117,532) uncovered an additional 19 novel variants. Conditional analysis identified 15 additional variants, 3 of which were novel. Little, if any, difference was seen when adjusting for putative QT interval lengthening medications genome-wide. Using multiple measurements in Genetic Epidemiology Research on Adult Health and Aging increased variance explained by 163%, and we show that the ≈6 measurements in Genetic Epidemiology Research on Adult Health and Aging was equivalent to a 2.4× increase in sample size of a design with a single measurement. The array heritability was estimated at ≈17%, approximately half of our estimate of 36% from family correlations. Heritability enrichment was estimated highest and most significant in cardiovascular tissue (enrichment 7.2, 95% CI = 5.7-8.7, P = 2.1e-10), and many of the novel variants included expression quantitative trait loci in heart and other relevant tissues. Comparing our results to other cardiac function traits, it appears that QT interval has a multifactorial genetic etiology.
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Affiliation(s)
- Thomas J Hoffmann
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94143, USA
| | - Meng Lu
- Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA
| | - Akinyemi Oni-Orisan
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA
- Department of Clinical Pharmacy, University of California San Francisco, San Francisco, CA 94143, USA
| | - Catherine Lee
- Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA
| | - Neil Risch
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94143, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA
| | - Carlos Iribarren
- Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA
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21
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Zang X, Zhang S, Li S, Wang X, Song W, Chen K, Ma J, Tu X, Xia Y, Zhao Y, Gao C. Evaluating Common NOS1AP Variants in Patients with Implantable Cardioverter Defibrillators for Secondary Prevention : Evaluating SNPs in NOS1AP. J Interv Card Electrophysiol 2022; 64:793-800. [PMID: 35353321 DOI: 0.1007/s10840-022-01137-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 01/25/2022] [Indexed: 08/11/2024]
Abstract
BACKGROUND Recent research has found that single nucleotide polymorphisms (SNPs) in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene are associated with altered QT intervals and sudden cardiac death (SCD). However, the clinical utility and implications of NOS1AP SNPs remain unclear. Thus, this study aimed to explore the influence of NOS1AP SNPs in patients with implantable cardioverter defibrillator (ICD) for secondary prevention. METHODS We conducted a case-control study to evaluate the most studied SNPs in NOS1AP (rs12143842, rs10494366, rs12567209, and rs16847548) in patients with ICD for secondary prevention. Patients were followed for up to 36 months from the time of ICD implantation. ICD interrogation data at 3 and 12 months, including rapid ventricular arrhythmia episodes and appropriate therapies, were then analyzed. RESULTS: A significant association was observed between rs10494366 and ICD recipients who experienced appropriate therapies. After a mean follow-up time of 31.70 ± 9.15 months, we detected significant differences among the three rs10494366 genotype groups in the distribution of ICD shocks and appropriate therapies, as well as in the correlation of rs10494366 and ICD shocks. According to Kaplan-Meier and Cox regression analyses, patients with the TT genotype had a higher risk of SCD than those with the GG genotype. CONCLUSIONS The present study revealed that NOS1AP SNP rs10494366 was associated with appropriate therapies. Specifically, the TT genotype increased ICD shocks and SCD risk in patients with ICD for secondary prevention for the first time.
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Affiliation(s)
- Xiaobiao Zang
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China
| | - Shulong Zhang
- Department of Cardiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Sisi Li
- Gannan Medical University, Jiangxi, China
| | - Xianqing Wang
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China
| | - Weifeng Song
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China
| | - Ke Chen
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China
| | - Jifang Ma
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China
| | - Xin Tu
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, China
| | - Yunlong Xia
- First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yonghui Zhao
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China.
| | - Chuanyu Gao
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China.
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22
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Abstract
Heart disease is the leading cause of death worldwide. Despite decades of research, most heart pathologies have limited treatments, and often the only curative approach is heart transplantation. Thus, there is an urgent need to develop new therapeutic approaches for treating cardiac diseases. Animal models that reproduce the human pathophysiology are essential to uncovering the biology of diseases and discovering therapies. Traditionally, mammals have been used as models of cardiac disease, but the cost of generating and maintaining new models is exorbitant, and the studies have very low throughput. In the last decade, the zebrafish has emerged as a tractable model for cardiac diseases, owing to several characteristics that made this animal popular among developmental biologists. Zebrafish fertilization and development are external; embryos can be obtained in high numbers, are cheap and easy to maintain, and can be manipulated to create new genetic models. Moreover, zebrafish exhibit an exceptional ability to regenerate their heart after injury. This review summarizes 25 years of research using the zebrafish to study the heart, from the classical forward screenings to the contemporary methods to model mutations found in patients with cardiac disease. We discuss the advantages and limitations of this model organism and introduce the experimental approaches exploited in zebrafish, including forward and reverse genetics and chemical screenings. Last, we review the models used to induce cardiac injury and essential ideas derived from studying natural regeneration. Studies using zebrafish have the potential to accelerate the discovery of new strategies to treat cardiac diseases.
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Affiliation(s)
- Juan Manuel González-Rosa
- Cardiovascular Research Center, Massachusetts General Hospital Research Institute, Harvard Medical School, Charlestown, MA
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23
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Zang X, Zhang S, Li S, Wang X, Song W, Chen K, Ma J, Tu X, Xia Y, Zhao Y, Gao C. Evaluating Common NOS1AP Variants in Patients with Implantable Cardioverter Defibrillators for Secondary Prevention : Evaluating SNPs in NOS1AP. J Interv Card Electrophysiol 2022; 64:793-800. [PMID: 35353321 DOI: 10.1007/s10840-022-01137-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 01/25/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Recent research has found that single nucleotide polymorphisms (SNPs) in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene are associated with altered QT intervals and sudden cardiac death (SCD). However, the clinical utility and implications of NOS1AP SNPs remain unclear. Thus, this study aimed to explore the influence of NOS1AP SNPs in patients with implantable cardioverter defibrillator (ICD) for secondary prevention. METHODS We conducted a case-control study to evaluate the most studied SNPs in NOS1AP (rs12143842, rs10494366, rs12567209, and rs16847548) in patients with ICD for secondary prevention. Patients were followed for up to 36 months from the time of ICD implantation. ICD interrogation data at 3 and 12 months, including rapid ventricular arrhythmia episodes and appropriate therapies, were then analyzed. RESULTS: A significant association was observed between rs10494366 and ICD recipients who experienced appropriate therapies. After a mean follow-up time of 31.70 ± 9.15 months, we detected significant differences among the three rs10494366 genotype groups in the distribution of ICD shocks and appropriate therapies, as well as in the correlation of rs10494366 and ICD shocks. According to Kaplan-Meier and Cox regression analyses, patients with the TT genotype had a higher risk of SCD than those with the GG genotype. CONCLUSIONS The present study revealed that NOS1AP SNP rs10494366 was associated with appropriate therapies. Specifically, the TT genotype increased ICD shocks and SCD risk in patients with ICD for secondary prevention for the first time.
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Affiliation(s)
- Xiaobiao Zang
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China
| | - Shulong Zhang
- Department of Cardiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Sisi Li
- Gannan Medical University, Jiangxi, China
| | - Xianqing Wang
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China
| | - Weifeng Song
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China
| | - Ke Chen
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China
| | - Jifang Ma
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China
| | - Xin Tu
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, China
| | - Yunlong Xia
- First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yonghui Zhao
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China.
| | - Chuanyu Gao
- Department of Cardiology, Peoples Hospital of Zhengzhou University Henan Provincial Peoples Hospital, Fuwai Central China Cardiovascular Hospital, Henan Province, Zhengzhou, China.
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24
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Ledford HA, Ren L, Thai PN, Park S, Timofeyev V, Sirish P, Xu W, Emigh AM, Priest JR, Perez MV, Ashley EA, Yarov-Yarovoy V, Yamoah EN, Zhang XD, Chiamvimonvat N. Disruption of protein quality control of the human ether-à-go-go related gene K + channel results in profound long QT syndrome. Heart Rhythm 2022; 19:281-292. [PMID: 34634443 PMCID: PMC8810706 DOI: 10.1016/j.hrthm.2021.10.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 09/20/2021] [Accepted: 10/04/2021] [Indexed: 11/04/2022]
Abstract
BACKGROUND Long QT syndrome (LQTS) is a hereditary disease that predisposes patients to life-threatening cardiac arrhythmias and sudden cardiac death. Our previous study of the human ether-à-go-go related gene (hERG)-encoded K+ channel (Kv11.1) supports an association between hERG and RING finger protein 207 (RNF207) variants in aggravating the onset and severity of LQTS, specifically T613M hERG (hERGT613M) and RNF207 frameshift (RNF207G603fs) mutations. However, the underlying mechanistic underpinning remains unknown. OBJECTIVE The purpose of the present study was to test the role of RNF207 in the function of hERG-encoded K+ channel subunits. METHODS Whole-cell patch-clamp experiments were performed in human embryonic kidney (HEK 293) cells and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) together with immunofluorescent confocal and high resolution microscopy, auto-ubiquitinylation assays, and co-immunoprecipitation experiments to test the functional interactions between hERG and RNF207. RESULTS Here, we demonstrated that RNF207 serves as an E3 ubiquitin ligase and targets misfolded hERGT613M proteins for degradation. RNF207G603fs exhibits decreased activity and hinders the normal degradation pathway; this increases the levels of hERGT613M subunits and their dominant-negative effect on the wild-type subunits, ultimately resulting in decreased current density. Similar findings are shown for hERGA614V, a known dominant-negative mutant subunit. Finally, the presence of RNF207G603fs with hERGT613M results in significantly prolonged action potential durations and reduced hERG current in human-induced pluripotent stem cell-derived cardiomyocytes. CONCLUSION Our study establishes RNF207 as an interacting protein serving as a ubiquitin ligase for hERG-encoded K+ channel subunits. Normal function of RNF207 is critical for the quality control of hERG subunits and consequently cardiac repolarization. Moreover, our study provides evidence for protein quality control as a new paradigm in life-threatening cardiac arrhythmias in patients with LQTS.
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Affiliation(s)
- Hannah A Ledford
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, Davis, California
| | - Lu Ren
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, Davis, California
| | - Phung N Thai
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, Davis, California
| | - Seojin Park
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, Davis, California; Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada
| | - Valeriy Timofeyev
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, Davis, California
| | - Padmini Sirish
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, Davis, California; Department of Veterans Affairs, Northern California Health Care System, Mather, California
| | - Wilson Xu
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, Davis, California
| | - Aiyana M Emigh
- Department of Physiology and Membrane Biology, University of California, Davis, Davis, California
| | - James R Priest
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California
| | - Marco V Perez
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California
| | - Euan A Ashley
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California
| | - Vladimir Yarov-Yarovoy
- Department of Physiology and Membrane Biology, University of California, Davis, Davis, California
| | - Ebenezer N Yamoah
- Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada
| | - Xiao-Dong Zhang
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, Davis, California; Department of Veterans Affairs, Northern California Health Care System, Mather, California.
| | - Nipavan Chiamvimonvat
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, Davis, California; Department of Veterans Affairs, Northern California Health Care System, Mather, California.
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25
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Thyroid hormones regulate cardiac repolarization and QT-interval related gene expression in hiPSC cardiomyocytes. Sci Rep 2022; 12:568. [PMID: 35022468 PMCID: PMC8755773 DOI: 10.1038/s41598-021-04659-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 12/22/2021] [Indexed: 11/08/2022] Open
Abstract
Prolongation of cardiac repolarization (QT interval) represents a dangerous and potentially life-threatening electrical event affecting the heart. Thyroid hormones (THs) are critical for cardiac development and heart function. However, little is known about THs influence on ventricular repolarization and controversial effects on QT prolongation are reported. Human iPSC-derived cardiomyocytes (hiPSC-CMs) and multielectrode array (MEA) systems were used to investigate the influence of 3,3',5-triiodo-L-Thyronine (T3) and 3,3',5,5'-tetraiodo-L-Thyronine (T4) on corrected Field Potential Duration (FPDc), the in vitro analog of QT interval, and on local extracellular Action Potential Duration (APD). Treatment with high THs doses induces a significant prolongation of both FPDc and APD, with the strongest increase reached after 24 h exposure. Preincubation with reverse T3 (rT3), a specific antagonist for nuclear TH receptor binding, significantly reduces T3 effects on FPDc, suggesting a TRs-mediated transcriptional mechanism. RNA-seq analysis showed significant deregulation in genes involved in cardiac repolarization pathways, including several QT-interval related genes. In conclusion, long-time administration of high THs doses induces FPDc prolongation in hiPSC-CMs probably through the modulation of genes linked to QT-interval regulation. These results open the way to investigate new potential diagnostic biomarkers and specific targeted therapies for cardiac repolarization dysfunctions.
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26
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In vivo identification and validation of novel potential predictors for human cardiovascular diseases. PLoS One 2021; 16:e0261572. [PMID: 34919578 PMCID: PMC8682894 DOI: 10.1371/journal.pone.0261572] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 12/03/2021] [Indexed: 12/30/2022] Open
Abstract
Genetics crucially contributes to cardiovascular diseases (CVDs), the global leading cause of death. Since the majority of CVDs can be prevented by early intervention there is a high demand for the identification of predictive causative genes. While genome wide association studies (GWAS) correlate genes and CVDs after diagnosis and provide a valuable resource for such causative candidate genes, often preferentially those with previously known or suspected function are addressed further. To tackle the unaddressed blind spot of understudied genes, we particularly focused on the validation of human heart phenotype-associated GWAS candidates with little or no apparent connection to cardiac function. Building on the conservation of basic heart function and underlying genetics from fish to human we combined CRISPR/Cas9 genome editing of the orthologs of human GWAS candidates in isogenic medaka with automated high-throughput heart rate analysis. Our functional analyses of understudied human candidates uncovered a prominent fraction of heart rate associated genes from adult human patients impacting on the heart rate in embryonic medaka already in the injected generation. Following this pipeline, we identified 16 GWAS candidates with potential diagnostic and predictive power for human CVDs.
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27
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Ng CA, Vandenberg JI. When it takes two to get one into trouble. Heart Rhythm 2021; 19:293-294. [PMID: 34687922 DOI: 10.1016/j.hrthm.2021.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 10/18/2021] [Indexed: 11/04/2022]
Affiliation(s)
- Chai-Ann Ng
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia, and St Vincent's Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia
| | - Jamie I Vandenberg
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia, and St Vincent's Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia.
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28
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Koch D, Alexandrovich A, Funk F, Kho AL, Schmitt JP, Gautel M. Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamers. Cell Rep 2021; 36:109448. [PMID: 34320358 PMCID: PMC8333238 DOI: 10.1016/j.celrep.2021.109448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 04/16/2021] [Accepted: 07/05/2021] [Indexed: 02/07/2023] Open
Abstract
Phospholamban (PLN) is an important regulator of cardiac calcium handling due to its ability to inhibit the calcium ATPase SERCA. β-Adrenergic stimulation reverses SERCA inhibition via PLN phosphorylation and facilitates fast calcium reuptake. PLN also forms pentamers whose physiological significance has remained elusive. Using mathematical modeling combined with biochemical and cell biological experiments, we show that pentamers regulate both the dynamics and steady-state levels of monomer phosphorylation. Substrate competition by pentamers and a feed-forward loop involving inhibitor-1 can delay monomer phosphorylation by protein kinase A (PKA), whereas cooperative pentamer dephosphorylation enables bistable PLN steady-state phosphorylation. Simulations show that phosphorylation delay and bistability act as complementary filters that reduce the effect of random fluctuations in PKA activity, thereby ensuring consistent monomer phosphorylation and SERCA activity despite noisy upstream signals. Preliminary analyses suggest that the PLN mutation R14del could impair noise filtering, offering a new perspective on how this mutation causes cardiac arrhythmias.
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Affiliation(s)
- Daniel Koch
- Randall Centre for Cell and Molecular Biophysics, King's College London, SE1 1UL London, UK.
| | | | - Florian Funk
- Institute of Pharmacology and Clinical Pharmacology, and Cardiovascular Research Institute Düsseldorf (CARID), University Hospital Düsseldorf, 40225 Düsseldorf, Germany
| | - Ay Lin Kho
- Randall Centre for Cell and Molecular Biophysics, King's College London, SE1 1UL London, UK
| | - Joachim P Schmitt
- Institute of Pharmacology and Clinical Pharmacology, and Cardiovascular Research Institute Düsseldorf (CARID), University Hospital Düsseldorf, 40225 Düsseldorf, Germany
| | - Mathias Gautel
- Randall Centre for Cell and Molecular Biophysics, King's College London, SE1 1UL London, UK
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29
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Magavern EF, Kaski JC, Turner RM, Drexel H, Janmohamed A, Scourfield A, Burrage D, Floyd CN, Adeyeye E, Tamargo J, Lewis BS, Kjeldsen KP, Niessner A, Wassmann S, Sulzgruber P, Borry P, Agewall S, Semb AG, Savarese G, Pirmohamed M, Caulfield MJ. The Role of Pharmacogenomics in Contemporary Cardiovascular Therapy: A position statement from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2021; 8:85-99. [PMID: 33638977 DOI: 10.1093/ehjcvp/pvab018] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/05/2021] [Accepted: 02/24/2021] [Indexed: 12/14/2022]
Abstract
There is a strong and ever-growing body of evidence regarding the use of pharmacogenomics to inform cardiovascular pharmacology. However, there is no common position taken by international cardiovascular societies to unite diverse availability, interpretation and application of such data, nor is there recognition of the challenges of variation in clinical practice between countries within Europe. Aside from the considerable barriers to implementing pharmacogenomic testing and the complexities of clinically actioning results, there are differences in the availability of resources and expertise internationally within Europe. Diverse legal and ethical approaches to genomic testing and clinical therapeutic application also require serious thought. As direct-to-consumer genomic testing becomes more common, it can be anticipated that data may be brought in by patients themselves, which will require critical assessment by the clinical cardiovascular prescriber. In a modern, pluralistic and multi-ethnic Europe, self-identified race/ethnicity may not be concordant with genetically detected ancestry and thus may not accurately convey polymorphism prevalence. Given the broad relevance of pharmacogenomics to areas such as thrombosis and coagulation, interventional cardiology, heart failure, arrhythmias, clinical trials, and policy/regulatory activity within cardiovascular medicine, as well as to genomic and pharmacology subspecialists, this position statement attempts to address these issues at a wide-ranging level.
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Affiliation(s)
- E F Magavern
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Department of Clinical Pharmacology, Cardiovascular Medicine, Barts Health NHS Trust, London, UK
| | - J C Kaski
- Molecular and Clinical Sciences Research Institute, St George's, University of London, United Kingdom
| | - R M Turner
- The Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, UK.,Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - H Drexel
- Vorarlberg Institute for Vascular Investigation & Treatment (VIVIT), Feldkirch, A Private University of the Principality of Liechtenstein, Triesen, FL.,Drexel University College of Medicine, Philadelphia, USA
| | - A Janmohamed
- Department of Clinical Pharmacology, St George's, University of London, United Kingdom
| | - A Scourfield
- Department of Clinical Pharmacology, University College London Hospital Foundation Trust, UK
| | - D Burrage
- Whittington Health NHS Trust, London, UK
| | - C N Floyd
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK.,Department of Clinical Pharmacology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - E Adeyeye
- Department of Clinical Pharmacology, Cardiovascular Medicine, Barts Health NHS Trust, London, UK
| | - J Tamargo
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense, Madrid, Spain
| | - B S Lewis
- Cardiovascular Clinical Research Institute, Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Keld Per Kjeldsen
- Department of Cardiology, Copenhagen University Hospital (Amager-Hvidovre), Copenhagen, Denmark.,Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
| | - A Niessner
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna
| | - S Wassmann
- Cardiology Pasing, Munich, Germany and University of the Saarland, Homburg/Saar, Germany
| | - P Sulzgruber
- Medical University of Vienna, Department of Medicine II, Division of Cardiology
| | - P Borry
- Center for Biomedical Ethics and Law, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium.,Leuven Institute for Human Genetics and Society, Leuven, Belgium
| | - S Agewall
- Oslo University Hospital Ullevål and Institute of Clinical Sciences, University of Oslo, Oslo, Norway
| | - A G Semb
- Preventive Cardio-Rheuma clinic, department of rheumatology, innovation and research, Diakonhjemmet hospital, Oslo, Norway
| | - G Savarese
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
| | - M Pirmohamed
- The Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, UK.,Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.,Liverpool Health Partners, Liverpool, UK
| | - M J Caulfield
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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30
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Majmundar AJ, Buerger F, Forbes TA, Klämbt V, Schneider R, Deutsch K, Kitzler TM, Howden SE, Scurr M, Tan KS, Krzeminski M, Widmeier E, Braun DA, Lai E, Ullah I, Amar A, Kolb A, Eddy K, Chen CH, Salmanullah D, Dai R, Nakayama M, Ottlewski I, Kolvenbach CM, Onuchic-Whitford AC, Mao Y, Mann N, Nabhan MM, Rosen S, Forman-Kay JD, Soliman NA, Heilos A, Kain R, Aufricht C, Mane S, Lifton RP, Shril S, Little MH, Hildebrandt F. Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice. SCIENCE ADVANCES 2021; 7:eabe1386. [PMID: 33523862 PMCID: PMC10763988 DOI: 10.1126/sciadv.abe1386] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/11/2020] [Indexed: 06/12/2023]
Abstract
Nephrotic syndrome (NS) is a leading cause of chronic kidney disease. We found recessive NOS1AP variants in two families with early-onset NS by exome sequencing. Overexpression of wild-type (WT) NOS1AP, but not cDNA constructs bearing patient variants, increased active CDC42 and promoted filopodia and podosome formation. Pharmacologic inhibition of CDC42 or its effectors, formin proteins, reduced NOS1AP-induced filopodia formation. NOS1AP knockdown reduced podocyte migration rate (PMR), which was rescued by overexpression of WT Nos1ap but not by constructs bearing patient variants. PMR in NOS1AP knockdown podocytes was also rescued by constitutively active CDC42Q61L or the formin DIAPH3 Modeling a NOS1AP patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. Nos1apEx3-/Ex3- mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis. These findings demonstrate that recessive NOS1AP variants impair CDC42/DIAPH-dependent actin remodeling, cause aberrant organoid glomerulogenesis, and lead to a glomerulopathy in humans and mice.
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Affiliation(s)
- Amar J Majmundar
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Florian Buerger
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Thomas A Forbes
- Kidney Development, Disease and Regeneration Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
- Department of Nephrology, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Verena Klämbt
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ronen Schneider
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Konstantin Deutsch
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Thomas M Kitzler
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
- The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Sara E Howden
- Kidney Development, Disease and Regeneration Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Michelle Scurr
- Kidney Development, Disease and Regeneration Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Ker Sin Tan
- Kidney Development, Disease and Regeneration Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Mickaël Krzeminski
- Molecular Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Eugen Widmeier
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Daniela A Braun
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ethan Lai
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ihsan Ullah
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ali Amar
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Amy Kolb
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kaitlyn Eddy
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Chin Heng Chen
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Daanya Salmanullah
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Rufeng Dai
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Makiko Nakayama
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Isabel Ottlewski
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Caroline M Kolvenbach
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ana C Onuchic-Whitford
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Youying Mao
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Nina Mann
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Marwa M Nabhan
- Department of Pediatrics, Center for Pediatric Nephrology and Transplantation, Kasr Al Ainy Medical School, Cairo University, Cairo, Egypt
| | - Seymour Rosen
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Julie D Forman-Kay
- Molecular Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - Neveen A Soliman
- Department of Pediatrics, Center for Pediatric Nephrology and Transplantation, Kasr Al Ainy Medical School, Cairo University, Cairo, Egypt
| | - Andreas Heilos
- Department of Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Renate Kain
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | | | - Shrikant Mane
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Richard P Lifton
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA
- Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA
| | - Shirlee Shril
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Melissa H Little
- Kidney Development, Disease and Regeneration Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Friedhelm Hildebrandt
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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31
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Turan NN, Moshal KS, Roder K, Baggett BC, Kabakov AY, Dhakal S, Teramoto R, Chiang DYE, Zhong M, Xie A, Lu Y, Dudley SC, MacRae CA, Karma A, Koren G. The endosomal trafficking regulator LITAF controls the cardiac Nav1.5 channel via the ubiquitin ligase NEDD4-2. J Biol Chem 2020; 295:18148-18159. [PMID: 33093176 PMCID: PMC7939464 DOI: 10.1074/jbc.ra120.015216] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 10/20/2020] [Indexed: 01/14/2023] Open
Abstract
The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current INa and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca2+ and Na+ homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation.
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Affiliation(s)
- Nilüfer N Turan
- Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Karni S Moshal
- Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Karim Roder
- Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Brett C Baggett
- Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Anatoli Y Kabakov
- Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Saroj Dhakal
- Physics Department and Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, Massachusetts, USA
| | - Ryota Teramoto
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - David Yi-Eng Chiang
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Mingwang Zhong
- Physics Department and Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, Massachusetts, USA
| | - An Xie
- Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Yichun Lu
- Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Samuel C Dudley
- Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Calum A MacRae
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Alain Karma
- Physics Department and Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, Massachusetts, USA
| | - Gideon Koren
- Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.
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32
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Pérez-Agustín A, Pinsach-Abuin M, Pagans S. Role of Non-Coding Variants in Brugada Syndrome. Int J Mol Sci 2020; 21:E8556. [PMID: 33202810 PMCID: PMC7698069 DOI: 10.3390/ijms21228556] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 12/15/2022] Open
Abstract
Brugada syndrome (BrS) is an inherited electrical heart disease associated with a high risk of sudden cardiac death (SCD). The genetic characterization of BrS has always been challenging. Although several cardiac ion channel genes have been associated with BrS, SCN5A is the only gene that presents definitive evidence for causality to be used for clinical diagnosis of BrS. However, more than 65% of diagnosed cases cannot be explained by variants in SCN5A or other genes. Therefore, in an important number of BrS cases, the underlying mechanisms are still elusive. Common variants, mostly located in non-coding regions, have emerged as potential modulators of the disease by affecting different regulatory mechanisms, including transcription factors (TFs), three-dimensional organization of the genome, or non-coding RNAs (ncRNAs). These common variants have been hypothesized to modulate the interindividual susceptibility of the disease, which could explain incomplete penetrance of BrS observed within families. Altogether, the study of both common and rare variants in parallel is becoming increasingly important to better understand the genetic basis underlying BrS. In this review, we aim to describe the challenges of studying non-coding variants associated with disease, re-examine the studies that have linked non-coding variants with BrS, and provide further evidence for the relevance of regulatory elements in understanding this cardiac disorder.
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Affiliation(s)
- Adrian Pérez-Agustín
- Department of Medical Sciences, School of Medicine, University of Girona, 17003 Girona, Spain;
- Biomedical Research Institute of Girona, 17190 Salt, Spain;
| | | | - Sara Pagans
- Department of Medical Sciences, School of Medicine, University of Girona, 17003 Girona, Spain;
- Biomedical Research Institute of Girona, 17190 Salt, Spain;
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33
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Kashiwa A, Aiba T, Makimoto H, Shimamoto K, Yamagata K, Kamakura T, Wada M, Miyamoto K, Inoue-Yamada Y, Ishibashi K, Noda T, Nagase S, Miyazaki A, Sakaguchi H, Shiraishi I, Yagihara N, Watanabe H, Aizawa Y, Makiyama T, Itoh H, Hayashi K, Yamagishi M, Sumitomo N, Yoshinaga M, Morita H, Ohe T, Miyamoto Y, Makita N, Yasuda S, Kusano K, Ohno S, Horie M, Shimizu W. Systematic Evaluation of KCNQ1 Variant Using ACMG/AMP Guidelines and Risk Stratification in Long QT Syndrome Type 1. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2020. [PMID: 32936022 DOI: 10.1161/circgen.120.002926] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background - Mutation/variant-site specific risk stratification in long-QT syndrome type 1 (LQT1) has been well investigated, but it is still challenging to adapt current enormous genomic information to clinical aspects caused by each mutation/variant. We assessed a novel variant-specific risk stratification in LQT1 patients. Methods - We classified a pathogenicity of 141 KCNQ1 variants among 927 LQT1 patients (536 probands) based on the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines and evaluated whether the ACMG/AMP-based classification was associated with arrhythmic risk in LQT1 patients. Results - Among 141 KCNQ1 variants, 61 (43.3%), 55 (39.0%), and 25 (17.7%) variants were classified into pathogenic (P), likely pathogenic (LP), and variant of unknown significance (VUS), respectively. Multivariable analysis showed that proband (HR = 2.53; 95%CI = 1.94-3.32; p <0.0001), longer QTc (≥500ms) (HR = 1.44; 95%CI = 1.13-1.83; p = 0.004), variants at membrane spanning (MS) (vs. those at N/C terminus) (HR = 1.42; 95%CI = 1.08-1.88; p = 0.01), C-loop (vs. N/C terminus) (HR = 1.52; 95%CI = 1.06-2.16; p = 0.02), and P variants [(vs. LP) (HR = 1.72; 95%CI = 1.32-2.26; p <0.0001), (vs. VUS) (HR = 1.81; 95%CI = 1.15-2.99; p = 0.009)] were significantly associated with syncopal events. The ACMG/AMP-based KCNQ1 evaluation was useful for risk stratification not only in family members but also in probands. A clinical score (0~4) based on proband, QTc (≥500ms), variant location (MS or C-loop) and P variant by ACMG/AMP guidelines allowed identification of patients more likely to have arrhythmic events. Conclusions - Comprehensive evaluation of clinical findings and pathogenicity of KCNQ1 variants based on the ACMG/AMP-based evaluation may stratify arrhythmic risk of congenital long-QT syndrome type 1.
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Affiliation(s)
- Asami Kashiwa
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita & Department of Cardiovascular & Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takeshi Aiba
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Hisaki Makimoto
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Keiko Shimamoto
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Kenichiro Yamagata
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Tsukasa Kamakura
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Mitsuru Wada
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Koji Miyamoto
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Yuko Inoue-Yamada
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Kohei Ishibashi
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Takashi Noda
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Satoshi Nagase
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Aya Miyazaki
- Department of Pediatric Cardiology, Shizuoka Children's Hospital, Shizuoka, Japan
| | - Heima Sakaguchi
- Department of Pediatric Cardiology, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Isao Shiraishi
- Department of Pediatric Cardiology, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Nobue Yagihara
- Department of Cardiovascular Biology & Medicine, Niigata University Graduate School of Medical & Dental Sciences, Niigata, Japan
| | - Hiroshi Watanabe
- Department of Cardiovascular Biology & Medicine, Niigata University Graduate School of Medical & Dental Sciences, Niigata, Japan
| | - Yoshifusa Aizawa
- Department of Cardiology, Tachikawa General Hospital, Niigata, Japan
| | - Takeru Makiyama
- Department of Cardiovascular & Medicine Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hideki Itoh
- Division of Patient Safety, Hiroshima University Hospital, Hiroshima, Japan
| | - Kenshi Hayashi
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine Science, Kanazawa, Japan
| | | | - Naotaka Sumitomo
- Department of Pediatric Cardiology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Masao Yoshinaga
- Department of Pediatrics, Kagoshima Medical Center, Kagoshima, Japan
| | - Hiroshi Morita
- Department of Cardiovascular Therapeutics, Okayama University Graduate School of Medicine, Okayama, Japan
| | - Tohru Ohe
- Department of Cardiovascular Therapeutics, Okayama University Graduate School of Medicine, Okayama, Japan
| | - Yoshihiro Miyamoto
- Division of Preventive Cardiology, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Naomasa Makita
- Omics Research Center, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Satoshi Yasuda
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Kengo Kusano
- Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan
| | - Seiko Ohno
- Department of Bioscience & Genetics, National Cerebral & Cardiovascular Center Suita, Japan
| | - Minoru Horie
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Wataru Shimizu
- Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan
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34
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Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 Regulation. Cell Rep 2020; 28:2704-2714.e5. [PMID: 31484079 DOI: 10.1016/j.celrep.2019.08.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 06/05/2019] [Accepted: 07/30/2019] [Indexed: 12/26/2022] Open
Abstract
The human ether-a-go-go-related gene KCNH2 encodes the voltage-gated potassium channel underlying IKr, a current critical for the repolarization phase of the cardiac action potential. Mutations in KCNH2 that cause a reduction of the repolarizing current can result in cardiac arrhythmias associated with long-QT syndrome. Here, we investigate the regulation of KCNH2 and identify multiple active enhancers. A transcribed enhancer ∼85 kbp downstream of Kcnh2 physically contacts the promoters of two Kcnh2 isoforms in a cardiac-specific manner in vivo. Knockdown of its ncRNA transcript results in reduced expression of Kcnh2b and two neighboring mRNAs, Nos3 and Abcb8, in vitro. Genomic deletion of the enhancer, including the ncRNA transcription start site, from the mouse genome causes a modest downregulation of both Kcnh2a and Kcnh2b in the ventricles. These findings establish that the regulation of Kcnh2a and Kcnh2b is governed by a complex regulatory landscape that involves multiple partially redundantly acting enhancers.
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35
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Tan WLW, Anene-Nzelu CG, Wong E, Lee CJM, Tan HS, Tang SJ, Perrin A, Wu KX, Zheng W, Ashburn RJ, Pan B, Lee MY, Autio MI, Morley MP, Tam WL, Cheung C, Margulies KB, Chen L, Cappola TP, Loh M, Chambers J, Prabhakar S, Foo RSY. Epigenomes of Human Hearts Reveal New Genetic Variants Relevant for Cardiac Disease and Phenotype. Circ Res 2020; 127:761-777. [PMID: 32529949 DOI: 10.1161/circresaha.120.317254] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
RATIONALE Identifying genetic markers for heterogeneous complex diseases such as heart failure is challenging and requires prohibitively large cohort sizes in genome-wide association studies to meet the stringent threshold of genome-wide statistical significance. On the other hand, chromatin quantitative trait loci, elucidated by direct epigenetic profiling of specific human tissues, may contribute toward prioritizing subthreshold variants for disease association. OBJECTIVE Here, we captured noncoding genetic variants by performing epigenetic profiling for enhancer H3K27ac chromatin immunoprecipitation followed by sequencing in 70 human control and end-stage failing hearts. METHODS AND RESULTS We have mapped a comprehensive catalog of 47 321 putative human heart enhancers and promoters. Three thousand eight hundred ninety-seven differential acetylation peaks (FDR [false discovery rate], 5%) pointed to pathways altered in heart failure. To identify cardiac histone acetylation quantitative trait loci (haQTLs), we regressed out confounding factors including heart failure disease status and used the G-SCI (Genotype-independent Signal Correlation and Imbalance) test1 to call out 1680 haQTLs (FDR, 10%). RNA sequencing performed on the same heart samples proved a subset of haQTLs to have significant association also to gene expression (expression quantitative trait loci), either in cis (180) or through long-range interactions (81), identified by Hi-C (high-throughput chromatin conformation assay) and HiChIP (high-throughput protein centric chromatin) performed on a subset of hearts. Furthermore, a concordant relationship between the gain or disruption of TF (transcription factor)-binding motifs, inferred from alternative alleles at the haQTLs, implied a surprising direct association between these specific TF and local histone acetylation in human hearts. Finally, 62 unique loci were identified by colocalization of haQTLs with the subthreshold loci of heart-related genome-wide association studies datasets. CONCLUSIONS Disease and phenotype association for 62 unique loci are now implicated. These loci may indeed mediate their effect through modification of enhancer H3K27 acetylation enrichment and their corresponding gene expression differences (bioRxiv: https://doi.org/10.1101/536763). Graphical Abstract: A graphical abstract is available for this article.
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Affiliation(s)
- Wilson Lek Wen Tan
- From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.)
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
| | - Chukwuemeka George Anene-Nzelu
- From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.)
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
| | - Eleanor Wong
- From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.)
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
| | - Chang Jie Mick Lee
- From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.)
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
| | - Hui San Tan
- From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.)
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
| | - Sze Jing Tang
- Cancer Science Institute of Singapore, National University of Singapore (S.J.T., W.L.T., L.C.)
| | - Arnaud Perrin
- From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.)
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
| | - Kan Xing Wu
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (K.X.W., C.C., M.L., J.C.)
| | - Wenhao Zheng
- From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.)
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
| | - Robert John Ashburn
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
| | - Bangfen Pan
- From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.)
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
| | - May Yin Lee
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
| | - Matias Ilmari Autio
- From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.)
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
| | - Michael P Morley
- Cardiovascular Institute, Perlman School of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (M.P.M., K.B.M., T.P.C.)
| | - Wai Leong Tam
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
- Cancer Science Institute of Singapore, National University of Singapore (S.J.T., W.L.T., L.C.)
| | - Christine Cheung
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (K.X.W., C.C., M.L., J.C.)
- Institute of Molecular and Cell Biology, Singapore (C.C.)
| | - Kenneth B Margulies
- Cardiovascular Institute, Perlman School of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (M.P.M., K.B.M., T.P.C.)
| | - Leilei Chen
- Cancer Science Institute of Singapore, National University of Singapore (S.J.T., W.L.T., L.C.)
| | - Thomas P Cappola
- Cardiovascular Institute, Perlman School of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (M.P.M., K.B.M., T.P.C.)
| | - Marie Loh
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (K.X.W., C.C., M.L., J.C.)
- Epidemiology and Biostatistics, Imperial College London (M.L., J.C.), United Kingdom
- Imperial College Healthcare NHS Trust, London, United Kingdom (M.L., J.C.)
| | - John Chambers
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (K.X.W., C.C., M.L., J.C.)
- Epidemiology and Biostatistics, Imperial College London (M.L., J.C.), United Kingdom
- Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, United Kingdom (J.C.)
- Imperial College Healthcare NHS Trust, London, United Kingdom (M.L., J.C.)
| | - Shyam Prabhakar
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
| | - Roger S Y Foo
- From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.)
- Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.)
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Turkowski KL, Dotzler SM, Tester DJ, Giudicessi JR, Bos JM, Speziale AD, Vollenweider JM, Ackerman MJ. Corrected QT Interval–Polygenic Risk Score and Its Contribution to Type 1, Type 2, and Type 3 Long-QT Syndrome in Probands and Genotype-Positive Family Members. CIRCULATION-GENOMIC AND PRECISION MEDICINE 2020; 13:e002922. [DOI: 10.1161/circgen.120.002922] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background:
Long-QT syndrome (LQTS) is characterized by a prolonged heart rate–corrected QT interval (QTc). Genome-wide association studies identified common genetic variants that collectively explain ≈8% to 10% of QTc variation in the general population.
Methods:
Overall, 423 patients with LQT1, LQT2, or LQT3 were genotyped for 61 QTc-associated genetic variants used in a prototype QTc–polygenic risk score (QTc-PRS). A weighted QTc-PRS (range, 0–154.8 ms) was calculated for each patient, and the FHS (Framingham Heart Study) population-based reference cohort (n=853).
Results:
The average QTc-PRS in LQTS was 88.0±7.2 and explained only ≈2.0% of the QTc variability. The QTc-PRS in LQTS probands (n=137; 89.3±6.8) was significantly greater than both FHS controls (87.2±7.4, difference-in-means±SE: 2.1±0.7,
P
<0.002) and LQTS genotype-positive family members (87.5±7.4, difference-in-mean, 1.8±.7,
P
<0.009). There was no difference in QTc-PRS between symptomatic (n=156, 88.6±7.3) and asymptomatic patients (n=267; 87.7±7.2, difference-in-mean, 0.9±0.7, P=0.15). LQTS patients with a QTc≥480 ms (n=120) had a significantly higher QTc-PRS (89.3±6.7) than patients with a QTc<480 ms (n=303, 87.6±7.4, difference-in-mean, 1.7±0.8,
P
<0.05). There was no difference in QTc-PRS or QTc between genotypes.
Conclusions:
The QTc-PRS explained <2% of the QTc variability in our LQT1, LQT2, and LQT3 cohort, contributing 5× less to their QTc value than in the general population. This prototype QTc-PRS does not distinguish/predict the clinical outcomes of individuals with LQTS.
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Affiliation(s)
- Kari L. Turkowski
- Mayo Clinic Graduate School of Biomedical Sciences (K.L.T., S.M.D.), Mayo Clinic, Rochester, MN, USA
- Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics (K.L.T., S.M.D., D.J.T., J.M.B., M.J.A.), Mayo Clinic, Rochester, MN, USA
| | - Steven M. Dotzler
- Mayo Clinic Graduate School of Biomedical Sciences (K.L.T., S.M.D.), Mayo Clinic, Rochester, MN, USA
- Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics (K.L.T., S.M.D., D.J.T., J.M.B., M.J.A.), Mayo Clinic, Rochester, MN, USA
| | - David J. Tester
- Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics (K.L.T., S.M.D., D.J.T., J.M.B., M.J.A.), Mayo Clinic, Rochester, MN, USA
| | - John R. Giudicessi
- Clinician-Investigator Training Program, Department of Cardiovascular Medicine (J.R.G.), Mayo Clinic, Rochester, MN, USA
| | - J. Martijn Bos
- Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics (K.L.T., S.M.D., D.J.T., J.M.B., M.J.A.), Mayo Clinic, Rochester, MN, USA
- Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (J.M.B., M.J.A.), Mayo Clinic, Rochester, MN, USA
| | - Ashley D. Speziale
- Medical Genome Facility (A.D.S., J.M.V.), Mayo Clinic, Rochester, MN, USA
| | | | - Michael J. Ackerman
- Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics (K.L.T., S.M.D., D.J.T., J.M.B., M.J.A.), Mayo Clinic, Rochester, MN, USA
- Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic, Department of Cardiovascular Medicine (M.J.A.), Mayo Clinic, Rochester, MN, USA
- Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (J.M.B., M.J.A.), Mayo Clinic, Rochester, MN, USA
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37
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Landstrom AP, Shah SH. Rare Things Being Common: Implications for Common Genetic Variants in Rare Diseases Like Long-QT Syndrome. Circulation 2020; 142:339-341. [PMID: 32718255 DOI: 10.1161/circulationaha.120.048339] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Andrew P Landstrom
- Department of Pediatrics (A.P.L.), Duke University School of Medicine, Durham, NC.,Division of Cardiology, Department of Cell Biology (A.P.L.), Duke University School of Medicine, Durham, NC
| | - Svati H Shah
- Department of Medicine (S.H.S.), Duke University School of Medicine, Durham, NC.,Duke Molecular Physiology Institute (S.H.S.), Duke University School of Medicine, Durham, NC
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38
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Elmén L, Volpato CB, Kervadec A, Pineda S, Kalvakuri S, Alayari NN, Foco L, Pramstaller PP, Ocorr K, Rossini A, Cammarato A, Colas AR, Hicks AA, Bodmer R. Silencing of CCR4-NOT complex subunits affects heart structure and function. Dis Model Mech 2020; 13:dmm044727. [PMID: 32471864 PMCID: PMC7390626 DOI: 10.1242/dmm.044727] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 05/19/2020] [Indexed: 12/12/2022] Open
Abstract
The identification of genetic variants that predispose individuals to cardiovascular disease and a better understanding of their targets would be highly advantageous. Genome-wide association studies have identified variants that associate with QT-interval length (a measure of myocardial repolarization). Three of the strongest associating variants (single-nucleotide polymorphisms) are located in the putative promotor region of CNOT1, a gene encoding the central CNOT1 subunit of CCR4-NOT: a multifunctional, conserved complex regulating gene expression and mRNA stability and turnover. We isolated the minimum fragment of the CNOT1 promoter containing all three variants from individuals homozygous for the QT risk alleles and demonstrated that the haplotype associating with longer QT interval caused reduced reporter expression in a cardiac cell line, suggesting that reduced CNOT1 expression might contribute to abnormal QT intervals. Systematic siRNA-mediated knockdown of CCR4-NOT components in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) revealed that silencing CNOT1 and other CCR4-NOT genes reduced their proliferative capacity. Silencing CNOT7 also shortened action potential duration. Furthermore, the cardiac-specific knockdown of Drosophila orthologs of CCR4-NOT genes in vivo (CNOT1/Not1 and CNOT7/8/Pop2) was either lethal or resulted in dilated cardiomyopathy, reduced contractility or a propensity for arrhythmia. Silencing CNOT2/Not2, CNOT4/Not4 and CNOT6/6L/twin also affected cardiac chamber size and contractility. Developmental studies suggested that CNOT1/Not1 and CNOT7/8/Pop2 are required during cardiac remodeling from larval to adult stages. To summarize, we have demonstrated how disease-associated genes identified by GWAS can be investigated by combining human cardiomyocyte cell-based and whole-organism in vivo heart models. Our results also suggest a potential link of CNOT1 and CNOT7/8 to QT alterations and further establish a crucial role of the CCR4-NOT complex in heart development and function.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Lisa Elmén
- Development Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Claudia B Volpato
- Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Via Galvani 31, 39100 Bolzano, Italy
| | - Anaïs Kervadec
- Development Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Santiago Pineda
- Development Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Sreehari Kalvakuri
- Development Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Nakissa N Alayari
- Development Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Luisa Foco
- Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Via Galvani 31, 39100 Bolzano, Italy
| | - Peter P Pramstaller
- Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Via Galvani 31, 39100 Bolzano, Italy
| | - Karen Ocorr
- Development Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Alessandra Rossini
- Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Via Galvani 31, 39100 Bolzano, Italy
| | - Anthony Cammarato
- Johns Hopkins University, Division of Cardiology, 720 Rutland Ave., Baltimore, MD 21205, USA
| | - Alexandre R Colas
- Development Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Andrew A Hicks
- Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Via Galvani 31, 39100 Bolzano, Italy
| | - Rolf Bodmer
- Development Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
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Ramírez J, van Duijvenboden S, Young WJ, Orini M, Lambiase PD, Munroe PB, Tinker A. Common Genetic Variants Modulate the Electrocardiographic Tpeak-to-Tend Interval. Am J Hum Genet 2020; 106:764-778. [PMID: 32386560 PMCID: PMC7273524 DOI: 10.1016/j.ajhg.2020.04.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 04/08/2020] [Indexed: 02/06/2023] Open
Abstract
Sudden cardiac death is responsible for half of all deaths from cardiovascular disease. The analysis of the electrophysiological substrate for arrhythmias is crucial for optimal risk stratification. A prolonged T-peak-to-Tend (Tpe) interval on the electrocardiogram is an independent predictor of increased arrhythmic risk, and Tpe changes with heart rate are even stronger predictors. However, our understanding of the electrophysiological mechanisms supporting these risk factors is limited. We conducted genome-wide association studies (GWASs) for resting Tpe and Tpe response to exercise and recovery in ∼30,000 individuals, followed by replication in independent samples (∼42,000 for resting Tpe and ∼22,000 for Tpe response to exercise and recovery), all from UK Biobank. Fifteen and one single-nucleotide variants for resting Tpe and Tpe response to exercise, respectively, were formally replicated. In a full dataset GWAS, 13 further loci for resting Tpe, 1 for Tpe response to exercise and 1 for Tpe response to exercise were genome-wide significant (p ≤ 5 × 10-8). Sex-specific analyses indicated seven additional loci. In total, we identify 32 loci for resting Tpe, 3 for Tpe response to exercise and 3 for Tpe response to recovery modulating ventricular repolarization, as well as cardiac conduction and contraction. Our findings shed light on the genetic basis of resting Tpe and Tpe response to exercise and recovery, unveiling plausible candidate genes and biological mechanisms underlying ventricular excitability.
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Affiliation(s)
- Julia Ramírez
- Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK
| | - Stefan van Duijvenboden
- Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK
| | - William J Young
- Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Barts Heart Centre, St Bartholomew's Hospital, London EC1A 7BE, UK
| | - Michele Orini
- Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK; Barts Heart Centre, St Bartholomew's Hospital, London EC1A 7BE, UK
| | - Pier D Lambiase
- Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK; Barts Heart Centre, St Bartholomew's Hospital, London EC1A 7BE, UK
| | - Patricia B Munroe
- Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
| | - Andrew Tinker
- Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
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40
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Li X, Guo LZ, Liu N, Du X, Bai R, Dong JZ, Ma CS. Association of T66A polymorphism in CASQ2 with PR interval in a Chinese population. Herz 2020; 46:123-129. [PMID: 32291483 DOI: 10.1007/s00059-020-04913-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 02/18/2020] [Accepted: 03/18/2020] [Indexed: 11/24/2022]
Abstract
OBJECTIVE The aim of this study was to explore the relationship between arrhythmia-associated or electrocardiogram (ECG)-associated common variants and PR interval, QRS duration, QTcorrected, and heart rate in a Chinese cohort. METHODS We studied the association between 26 single-nucleotide polymorphisms (SNPs) and digital ECG data from 379 unrelated Han Chinese individuals collected in an epidemiological survey in Beijing. All subjects were 45 years of age or older and were free of cardiovascular diseases and diabetes. The SNPs were genotyped in a multiplex panel using the Sequenom MassARRAY platform. RESULTS Missense variant T66A (Thr66Ala, rs4074536) of the CASQ2 gene, which was previously reported to be associated with QRS complex in European populations, was significantly associated with PR interval prolongation in our sample (padjusted = 0.006, betaadjusted = 3.983 ms). A two-tailed t test showed that the CC genotype (n = 86) had a significantly longer PR interval (162.9 ± 19.4 ms) than the non-CC genotypes (n = 288, PR interval: 154.6 ± 20.9 ms), with a remarkable difference of 8.2 ms between the groups (p = 0.001). Interestingly, this association between T66A of CASQ2 and PR interval was more evident in females (padjusted = 0.007, betaadjusted = 5.723 ms) than in males (padjusted = 0.177, betaadjusted = 2.725 ms). In addition, rs3822714 in the HAND1 locus might be associated with QRS duration (padjusted = 0.034, betaadjusted = -2.268 ms). CONCLUSION We identified a novel signal of an association between the CC genotype of T66A in CASQ2 and PR interval prolongation in a Chinese population, particularly in females. This association deserves further exploration given its possible effects on calcium handling in cardiac electrophysiology.
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Affiliation(s)
- Xin Li
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine for Cardiovascular Diseases, Beijing, China
| | - Li-Zhu Guo
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine for Cardiovascular Diseases, Beijing, China
| | - Nian Liu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine for Cardiovascular Diseases, Beijing, China
| | - Xin Du
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine for Cardiovascular Diseases, Beijing, China
| | - Rong Bai
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine for Cardiovascular Diseases, Beijing, China
| | - Jian-Zeng Dong
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine for Cardiovascular Diseases, Beijing, China
| | - Chang-Sheng Ma
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine for Cardiovascular Diseases, Beijing, China.
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41
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van den Brink L, Grandela C, Mummery CL, Davis RP. Inherited cardiac diseases, pluripotent stem cells, and genome editing combined-the past, present, and future. Stem Cells 2020; 38:174-186. [PMID: 31664757 PMCID: PMC7027796 DOI: 10.1002/stem.3110] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 10/09/2019] [Indexed: 12/15/2022]
Abstract
Research on mechanisms underlying monogenic cardiac diseases such as primary arrhythmias and cardiomyopathies has until recently been hampered by inherent limitations of heterologous cell systems, where mutant genes are expressed in noncardiac cells, and physiological differences between humans and experimental animals. Human-induced pluripotent stem cells (hiPSCs) have proven to be a game changer by providing new opportunities for studying the disease in the specific cell type affected, namely the cardiomyocyte. hiPSCs are particularly valuable because not only can they be differentiated into unlimited numbers of these cells, but they also genetically match the individual from whom they were derived. The decade following their discovery showed the potential of hiPSCs for advancing our understanding of cardiovascular diseases, with key pathophysiological features of the patient being reflected in their corresponding hiPSC-derived cardiomyocytes (the past). Now, recent advances in genome editing for repairing or introducing genetic mutations efficiently have enabled the disease etiology and pathogenesis of a particular genotype to be investigated (the present). Finally, we are beginning to witness the promise of hiPSC in personalized therapies for individual patients, as well as their application in identifying genetic variants responsible for or modifying the disease phenotype (the future). In this review, we discuss how hiPSCs could contribute to improving the diagnosis, prognosis, and treatment of an individual with a suspected genetic cardiac disease, thereby developing better risk stratification and clinical management strategies for these potentially lethal but treatable disorders.
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Affiliation(s)
- Lettine van den Brink
- Department of Anatomy and EmbryologyLeiden University Medical CenterRC LeidenThe Netherlands
| | - Catarina Grandela
- Department of Anatomy and EmbryologyLeiden University Medical CenterRC LeidenThe Netherlands
| | - Christine L. Mummery
- Department of Anatomy and EmbryologyLeiden University Medical CenterRC LeidenThe Netherlands
| | - Richard P. Davis
- Department of Anatomy and EmbryologyLeiden University Medical CenterRC LeidenThe Netherlands
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Mitchell RN, Ashar FN, Jarvelin M, Froguel P, Sotoodehnia N, Brody JA, Sebert S, Huikuri H, Rioux J, Goyette P, Newcomb CE, Junttila MJ, Arking DE. Effect of Sex and Underlying Disease on the Genetic Association of QT Interval and Sudden Cardiac Death. J Am Heart Assoc 2019; 8:e013751. [PMID: 31747862 PMCID: PMC6912973 DOI: 10.1161/jaha.119.013751] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 10/16/2019] [Indexed: 01/08/2023]
Abstract
Background Sudden cardiac death (SCD) accounts for ≈300 000 deaths annually in the United States. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease, while women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the genetics of QT interval duration. Using sex- and coronary artery disease-stratified analyses, we assess differences in genetic association between longer QT interval and SCD risk. Methods and Results We examined 2282 SCD subjects and 3561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic versus nonischemic) and by sex. We used logistic regression to test for association between the top QT interval-associated single-nucleotide polymorphism, rs12143842 (in the NOS1AP locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups. No statistically significant differences were observed between the sexes for associations with rs12143842, despite the odds ratio being higher in females across all subgroup analyses. Consistent with our hypothesis, female non-ischemics had the highest odds ratio point estimate for association between rs12143842 and SCD risk and male ischemics the lowest odds ratio point estimate (P=0.036 for difference). Similar trends were observed for the Mendelian randomization analysis. Conclusions While individual subgroup comparisons did not achieve traditional criteria for statistical significance, this study is consistent with the hypothesis that the causal association of longer QT interval on SCD risk is stronger in women and nonischemic individuals.
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Affiliation(s)
- Rebecca N. Mitchell
- Department of Genetic MedicineMcKusick‐Nathans InstituteJohns HopkinsBaltimoreMD
| | - Foram N. Ashar
- Department of Genetic MedicineMcKusick‐Nathans InstituteJohns HopkinsBaltimoreMD
| | - Marjo‐Riitta Jarvelin
- Center for Life Course Health ResearchFaculty of MedicineUniversity of OuluFinland
- Biocenter OuluUniversity of OuluFinland
- Unit of Primary Health CareOulu University HospitalOuluFinland
- Department of Epidemiology and BiostatisticsMRC‐PHE Centre for Environment and HealthSchool of Public HealthImperial College LondonLondonUnited Kingdom
- Department of Life SciencesCollege of Health and Life SciencesBrunel University LondonLondonUnited Kingdom
| | - Philippe Froguel
- Department of Epidemiology and BiostatisticsMRC‐PHE Centre for Environment and HealthSchool of Public HealthImperial College LondonLondonUnited Kingdom
| | - Nona Sotoodehnia
- Cardiovascular Health Research UnitDivision of CardiologyDepartments of Medicine and EpidemiologyUniversity of WashingtonSeattleWA
| | - Jennifer A. Brody
- Cardiovascular Health Research UnitUniversity of WashingtonSeattleWA
| | - Sylvain Sebert
- Center for Life Course Health ResearchFaculty of MedicineUniversity of OuluFinland
- Biocenter OuluUniversity of OuluFinland
- Department of Epidemiology and BiostatisticsMRC‐PHE Centre for Environment and HealthSchool of Public HealthImperial College LondonLondonUnited Kingdom
| | - Heikki Huikuri
- Research Unit of Internal MedicineMedical Research Center OuluUniversity of Oulu and Oulu University HospitalOuluFinland
| | - John Rioux
- Montreal Heart InstituteUniversity of MontrealCanada
| | | | - Charles E. Newcomb
- Department of Genetic MedicineMcKusick‐Nathans InstituteJohns HopkinsBaltimoreMD
| | - M. Juhani Junttila
- Research Unit of Internal MedicineMedical Research Center OuluUniversity of Oulu and Oulu University HospitalOuluFinland
| | - Dan E. Arking
- Department of Genetic MedicineMcKusick‐Nathans InstituteJohns HopkinsBaltimoreMD
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43
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Pott A, Rottbauer W, Just S. Streamlining drug discovery assays for cardiovascular disease using zebrafish. Expert Opin Drug Discov 2019; 15:27-37. [PMID: 31570020 DOI: 10.1080/17460441.2020.1671351] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: In the last decade, our armamentarium of cardiovascular drug therapy has expanded significantly. Using innovative functional genomics strategies such as genome editing by CRISPR/Cas9 as well as high-throughput assays to identify bioactive small chemical compounds has significantly facilitated elaboration of the underlying pathomechanism in various cardiovascular diseases. However, despite scientific progress approvals for cardiovascular drugs has stagnated significantly compared to other fields of drug discovery and therapy during the past years.Areas covered: In this review, the authors discuss the aspects and pitfalls during the early phase of cardiovascular drug discovery and describe the advantages of zebrafish as an in vivo organism to model human cardiovascular diseases (CVD) as well as an in vivo platform for high-throughput chemical compound screening. They also highlight the emerging, promising techniques of automated read-out systems during high-throughput screening (HTS) for the evaluation of important cardiac functional parameters in zebrafish with the potential to streamline CVD drug discovery.Expert opinion: The successful identification of novel drugs to treat CVD is a major challenge in modern biomedical and clinical research. In this context, the definition of the etiologic fundamentals of human cardiovascular diseases is the prerequisite for an efficient and straightforward drug discovery.
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Affiliation(s)
- Alexander Pott
- Internal Medicine II, Ulm University Medical Center, Ulm, Germany.,Molecular Cardiology, Internal Medicine II, Ulm University Medical Center, Ulm, Germany
| | | | - Steffen Just
- Molecular Cardiology, Internal Medicine II, Ulm University Medical Center, Ulm, Germany
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44
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Moshal KS, Roder K, Kabakov AY, Werdich AA, Yi-Eng Chiang D, Turan NN, Xie A, Kim TY, Cooper LL, Lu Y, Zhong M, Li W, Terentyev D, Choi BR, Karma A, MacRae CA, Koren G. LITAF (Lipopolysaccharide-Induced Tumor Necrosis Factor) Regulates Cardiac L-Type Calcium Channels by Modulating NEDD (Neural Precursor Cell Expressed Developmentally Downregulated Protein) 4-1 Ubiquitin Ligase. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2019; 12:407-420. [PMID: 31462068 PMCID: PMC6750970 DOI: 10.1161/circgen.119.002641] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 07/19/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND The turnover of cardiac ion channels underlying action potential duration is regulated by ubiquitination. Genome-wide association studies of QT interval identified several single-nucleotide polymorphisms located in or near genes involved in protein ubiquitination. A genetic variant upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor) gene prompted us to determine its role in modulating cardiac excitation. METHODS Optical mapping was performed in zebrafish hearts to determine Ca2+ transients. Live-cell confocal calcium imaging was performed on adult rabbit cardiomyocytes to determine intracellular Ca2+handling. L-type calcium channel (LTCC) current (ICa,L) was measured using whole-cell recording. To study the effect of LITAF on Cav1.2 (L-type voltage-gated calcium channel 1.2) channel expression, surface biotinylation, and Westerns were performed. LITAF interactions were studied using coimmunoprecipitation and in situ proximity ligation assay. RESULTS LITAF knockdown in zebrafish resulted in a robust increase in calcium transients. Overexpressed LITAF in 3-week-old rabbit cardiomyocytes resulted in a decrease in ICa,L and Cavα1c abundance, whereas LITAF knockdown increased ICa,L and Cavα1c protein. LITAF-overexpressing decreases calcium transients in adult rabbit cardiomyocytes, which was associated with lower Cavα1c levels. In tsA201 cells, overexpressed LITAF downregulated total and surface pools of Cavα1c via increased Cavα1c ubiquitination and its subsequent lysosomal degradation. We observed colocalization between LITAF and LTCC in tsA201 and cardiomyocytes. In tsA201, NEDD (neural precursor cell expressed developmentally downregulated protein) 4-1, but not its catalytically inactive form NEDD4-1-C867A, increased Cavα1c ubiquitination. Cavα1c ubiquitination was further increased by coexpressed LITAF and NEDD4-1 but not NEDD4-1-C867A. NEDD4-1 knockdown abolished the negative effect of LITAF on ICa,L and Cavα1c levels in 3-week-old rabbit cardiomyocytes. Computer simulations demonstrated that a decrease of ICa,L current associated with LITAF overexpression simultaneously shortened action potential duration and decreased calcium transients in rabbit cardiomyocytes. CONCLUSIONS LITAF acts as an adaptor protein promoting NEDD4-1-mediated ubiquitination and subsequent degradation of LTCC, thereby controlling LTCC membrane levels and function and thus cardiac excitation.
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Affiliation(s)
- Karni S. Moshal
- Cardiovascular Research Center, Division of Cardiology, Dept of Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown Univ, Providence, RI
| | - Karim Roder
- Cardiovascular Research Center, Division of Cardiology, Dept of Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown Univ, Providence, RI
| | - Anatoli Y. Kabakov
- Cardiovascular Research Center, Division of Cardiology, Dept of Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown Univ, Providence, RI
| | - Andreas A. Werdich
- Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - David Yi-Eng Chiang
- Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Nilüfer N. Turan
- Cardiovascular Research Center, Division of Cardiology, Dept of Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown Univ, Providence, RI
| | - An Xie
- Cardiovascular Research Center, Division of Cardiology, Dept of Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown Univ, Providence, RI
| | - Tae Yun Kim
- Cardiovascular Research Center, Division of Cardiology, Dept of Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown Univ, Providence, RI
| | | | - Yichun Lu
- Cardiovascular Research Center, Division of Cardiology, Dept of Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown Univ, Providence, RI
| | - Mingwang Zhong
- Physics Dept & Center for Interdisciplinary Research in Complex Systems, Northeastern Univ, Boston, MA
| | - Weiyan Li
- Cardiovascular Research Center, Division of Cardiology, Dept of Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown Univ, Providence, RI
| | - Dmitry Terentyev
- Cardiovascular Research Center, Division of Cardiology, Dept of Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown Univ, Providence, RI
| | - Bum-Rak Choi
- Cardiovascular Research Center, Division of Cardiology, Dept of Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown Univ, Providence, RI
| | - Alain Karma
- Physics Dept & Center for Interdisciplinary Research in Complex Systems, Northeastern Univ, Boston, MA
| | - Calum A. MacRae
- Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Gideon Koren
- Cardiovascular Research Center, Division of Cardiology, Dept of Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown Univ, Providence, RI
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45
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Zang X, Li S, Zhao Y, Chen K, Wang X, Song W, Ma J, Tu X, Xia Y, Zhang S, Gao C. Systematic Meta-Analysis of the Association Between a Common NOS1AP Genetic Polymorphism, the QTc Interval, and Sudden Death. Int Heart J 2019; 60:1083-1090. [PMID: 31447468 DOI: 10.1536/ihj.19-024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Contemporary studies have identified rs10494366 in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene as a new genetic marker in modulating the QT interval and sudden cardiac death (SCD) in general populations. However, the conclusions were not coincident. Therefore, we conducted for the first time a system evaluation of the relativity of rs10494366, the QT interval, and sudden death by meta-analysis. In our study, the meta-analysis displayed the GG genotype of rs10494366 correlated with the QT interval in women with no heterogeneity, and in diabetes mellitus (DM) patients with minor heterogeneity. In the Caucasian population, the correlation of rs10494366 and sudden death was significant. The heterogeneity referred to the relevance between rs10494366 and sudden death in the Asian population. In conclusion, the minor allele of rs10494366 may have an impact on the QT interval in women or DM patients and may have a potential role in sudden death in the Caucasian population.
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Affiliation(s)
- Xiaobiao Zang
- Zhengzhou University People's Hospital, Fuwai Central China Cardiovascular Hospital, Zhengzhou University
| | | | - Yonghui Zhao
- Zhengzhou University People's Hospital, Fuwai Central China Cardiovascular Hospital, Zhengzhou University
| | - Ke Chen
- Zhengzhou University People's Hospital, Fuwai Central China Cardiovascular Hospital, Zhengzhou University
| | - Xianqing Wang
- Zhengzhou University People's Hospital, Fuwai Central China Cardiovascular Hospital, Zhengzhou University
| | - Weifeng Song
- Zhengzhou University People's Hospital, Fuwai Central China Cardiovascular Hospital, Zhengzhou University
| | - Jifang Ma
- Zhengzhou University People's Hospital, Fuwai Central China Cardiovascular Hospital, Zhengzhou University
| | - Xin Tu
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology
| | - Yunlong Xia
- First Affiliated Hospital of Dalian Medical University
| | - Shulong Zhang
- Department of Cardiology, Affiliated Zhongshan Hospital of Dalian University
| | - Chuanyu Gao
- Zhengzhou University People's Hospital, Fuwai Central China Cardiovascular Hospital, Zhengzhou University
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46
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Cerrone M, Remme CA, Tadros R, Bezzina CR, Delmar M. Beyond the One Gene-One Disease Paradigm: Complex Genetics and Pleiotropy in Inheritable Cardiac Disorders. Circulation 2019; 140:595-610. [PMID: 31403841 DOI: 10.1161/circulationaha.118.035954] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inheritable cardiac disorders, which may be associated with cardiomyopathic changes, are often associated with increased risk of sudden death in the young. Early linkage analysis studies in Mendelian forms of these diseases, such as hypertrophic cardiomyopathy and long-QT syndrome, uncovered large-effect genetic variants that contribute to the phenotype. In more recent years, through genotype-phenotype studies and methodological advances in genetics, it has become evident that most inheritable cardiac disorders are not monogenic but, rather, have a complex genetic basis wherein multiple genetic variants contribute (oligogenic or polygenic inheritance). Conversely, studies on genes underlying these disorders uncovered pleiotropic effects, with a single gene affecting multiple and apparently unrelated phenotypes. In this review, we explore these 2 phenomena: on the one hand, the evidence that variants in multiple genes converge to generate one clinical phenotype, and, on the other, the evidence that variants in one gene can lead to apparently unrelated phenotypes. Although multiple conditions are addressed to illustrate these concepts, the experience obtained in the study of long-QT syndrome, Brugada syndrome, and arrhythmogenic cardiomyopathy, and in the study of functions related to SCN5A (the gene coding for the α-subunit of the most abundant sodium channel in the heart) and PKP2 (the gene coding for the desmosomal protein plakophilin-2), as well, is discussed in more detail.
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Affiliation(s)
- Marina Cerrone
- Leon H. Charney Division of Cardiology (M.C., M.D.), NYU School of Medicine, New York.,Inherited Arrhythmias Clinic and Heart Rhythm Center, Leon H. Charney Division of Cardiology (M.C.), NYU School of Medicine, New York
| | - Carol Ann Remme
- Inherited Arrhythmias Clinic and Heart Rhythm Center, Leon H. Charney Division of Cardiology (M.C.), NYU School of Medicine, New York
| | - Rafik Tadros
- Amsterdam UMC, University of Amsterdam, Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, AMC Heart Center, The Netherlands (C.A.R., C.R.B.)
| | - Connie R Bezzina
- Inherited Arrhythmias Clinic and Heart Rhythm Center, Leon H. Charney Division of Cardiology (M.C.), NYU School of Medicine, New York
| | - Mario Delmar
- Leon H. Charney Division of Cardiology (M.C., M.D.), NYU School of Medicine, New York
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47
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van der Ende MY, Said MA, van Veldhuisen DJ, Verweij N, van der Harst P. Genome-wide studies of heart failure and endophenotypes: lessons learned and future directions. Cardiovasc Res 2019; 114:1209-1225. [PMID: 29912321 DOI: 10.1093/cvr/cvy083] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 04/16/2018] [Indexed: 12/28/2022] Open
Abstract
Heart failure (HF) is a complex clinical syndrome resulting from structural or functional impairments of ventricular filling or ejection of blood. HF has a poor prognosis and the burden to society remains tremendous. The unfulfilled expectation is that expanding our knowledge of the genetic architecture of HF will help to quickly advance the quality of risk assessment, diagnoses, and treatment. To date, genome-wide association studies (GWAS) of HF have led to disappointing results with only limited progress in our understanding and tempering the earlier expectations. However, the analyses of traits closely related to HF (also called 'endophenotypes') have led to promising and novel findings. For example, GWAS of NT-proBNP levels not only identified variants in the NNPA-NPPB locus but also substantiated data suggesting that natriuretic peptides in itself are associated with a lower risk of hypertension and HF. Many other genetic associates currently await experimental follow-up in which genes are prioritized based on bioinformatic analyses and various model organisms are employed to obtain functional insights. Promising genes with identified function could later be used in personalized medicine. Also, targeting specific pathogenic gene mutations is promising to protect future generations from HF, such as recently done in human embryos carrying the cardiomyopathy-associated MYBPC3 mutation. This review discusses the current status of GWAS of HF and its endophenotypes. In addition, future directions such as functional follow-up and application of GWAS results are discussed.
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Affiliation(s)
- Maaike Yldau van der Ende
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, RB Groningen, The Netherlands
| | - Mir Abdullah Said
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, RB Groningen, The Netherlands
| | - Dirk Jan van Veldhuisen
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, RB Groningen, The Netherlands
| | - Niek Verweij
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, RB Groningen, The Netherlands
| | - Pim van der Harst
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, RB Groningen, The Netherlands
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48
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van Setten J, Verweij N, Mbarek H, Niemeijer MN, Trompet S, Arking DE, Brody JA, Gandin I, Grarup N, Hall LM, Hemerich D, Lyytikäinen LP, Mei H, Müller-Nurasyid M, Prins BP, Robino A, Smith AV, Warren HR, Asselbergs FW, Boomsma DI, Caulfield MJ, Eijgelsheim M, Ford I, Hansen T, Harris TB, Heckbert SR, Hottenga JJ, Iorio A, Kors JA, Linneberg A, MacFarlane PW, Meitinger T, Nelson CP, Raitakari OT, Silva Aldana CT, Sinagra G, Sinner M, Soliman EZ, Stoll M, Uitterlinden A, van Duijn CM, Waldenberger M, Alonso A, Gasparini P, Gudnason V, Jamshidi Y, Kääb S, Kanters JK, Lehtimäki T, Munroe PB, Peters A, Samani NJ, Sotoodehnia N, Ulivi S, Wilson JG, de Geus EJC, Jukema JW, Stricker B, van der Harst P, de Bakker PIW, Isaacs A. Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits. Eur J Hum Genet 2019; 27:952-962. [PMID: 30679814 PMCID: PMC6777533 DOI: 10.1038/s41431-018-0295-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 10/05/2018] [Accepted: 10/16/2018] [Indexed: 01/09/2023] Open
Abstract
Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.
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Affiliation(s)
- Jessica van Setten
- Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
| | - Niek Verweij
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Hamdi Mbarek
- Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | | | - Stella Trompet
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Dan E Arking
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jennifer A Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
| | | | - Niels Grarup
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Leanne M Hall
- Department of Cardiovascular Sciences, University of Leicester, Leicester, England
- NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Groby Road, Leicester, UK
| | - Daiane Hemerich
- Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
- CAPES Foundation, Ministry of Education of Brazil, Brasília, DF, 70040-020, Brazil
| | - Leo-Pekka Lyytikäinen
- Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, 33520, Tampere, Finland
| | - Hao Mei
- Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Martina Müller-Nurasyid
- Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- Department of Medicine I, Ludwig-Maximilians-Universität, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany
| | - Bram P Prins
- Human Genetics Research Centre, ICCS, St George's University of London, London, UK
| | - Antonietta Robino
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Albert V Smith
- Icelandic Heart Association, Kopavogur, Iceland
- Faculty of Medicine, University of Iceland, Reykavik, Iceland
| | - Helen R Warren
- William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
- NIHR Barts Cardiovascular Research Centre, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Folkert W Asselbergs
- Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
- Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, The Netherlands
- Institute of Cardiovascular Science, Faculty of Population Health Sciences, and Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, UK
| | - Dorret I Boomsma
- Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Mark J Caulfield
- William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
- NIHR Barts Cardiovascular Research Centre, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Mark Eijgelsheim
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
- Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands
| | - Ian Ford
- Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK
| | - Torben Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tamara B Harris
- Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, MD, USA
| | - Susan R Heckbert
- Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Jouke-Jan Hottenga
- Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Annamaria Iorio
- Cardiovascular Department, "Ospedali Riuniti and University of Trieste", Trieste, Italy
| | - Jan A Kors
- Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Allan Linneberg
- Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital-The Capital Region, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Thomas Meitinger
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Human Genetics, Technische Universität München, Munich, Germany
| | - Christopher P Nelson
- Department of Cardiovascular Sciences, University of Leicester, Leicester, England
- NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Groby Road, Leicester, UK
| | - Olli T Raitakari
- Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, 20520, Finland
| | - Claudia T Silva Aldana
- Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Doctoral Program in Biomedical Sciences, Universidad del Rosario, Bogotá, Colombia
- Institute of translational Medicine-IMT-Center For Research in Genetics and Genomics-CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Rosario, Colombia
| | - Gianfranco Sinagra
- Cardiovascular Department, "Ospedali Riuniti and University of Trieste", Trieste, Italy
| | - Moritz Sinner
- Department of Medicine I, Ludwig-Maximilians-Universität, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Elsayed Z Soliman
- Epidemiological Cardiology Research Center (EPICARE), Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Monika Stoll
- CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
- Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands
- Department of Biochemistry, Maastricht University, Maastricht, The Netherlands
| | - Andre Uitterlinden
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Cornelia M van Duijn
- Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Melanie Waldenberger
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- Research unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Alvaro Alonso
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Paolo Gasparini
- DSM, University of Trieste, Trieste, Italy
- IRCCS-Burlo Garofolo Children Hospital, Via dell'Istria 65, Trieste, Italy
| | - Vilmundur Gudnason
- Icelandic Heart Association, Kopavogur, Iceland
- Faculty of Medicine, University of Iceland, Reykavik, Iceland
| | - Yalda Jamshidi
- Human Genetics Research Centre, ICCS, St George's University of London, London, UK
| | - Stefan Kääb
- Department of Medicine I, Ludwig-Maximilians-Universität, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Jørgen K Kanters
- Laboratory of Experimental Cardiology, University of Copenhagen, Copenhagen, Denmark
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, 33520, Tampere, Finland
| | - Patricia B Munroe
- William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
- NIHR Barts Cardiovascular Research Centre, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Annette Peters
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Diabetes Research, Neuherberg, Germany
| | - Nilesh J Samani
- Department of Cardiovascular Sciences, University of Leicester, Leicester, England
- NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Groby Road, Leicester, UK
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, WA, USA
| | - Sheila Ulivi
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - James G Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
| | - Eco J C de Geus
- Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - J Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Bruno Stricker
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Pim van der Harst
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands
| | - Paul I W de Bakker
- Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Aaron Isaacs
- CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
- Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands.
- Department of Biochemistry, Maastricht University, Maastricht, The Netherlands.
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El-Sherif N, Turitto G, Boutjdir M. Acquired Long QT Syndrome and Electrophysiology of Torsade de Pointes. Arrhythm Electrophysiol Rev 2019; 8:122-130. [PMID: 31114687 PMCID: PMC6528034 DOI: 10.15420/aer.2019.8.3] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 04/04/2019] [Indexed: 12/16/2022] Open
Abstract
Congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. Although congenital LQTS remains the domain of cardiologists, cardiac electrophysiologists and specialised centres, the much more frequently acquired LQTS is the domain of physicians and other members of healthcare teams required to make therapeutic decisions. This paper reviews the electrophysiological mechanisms of acquired LQTS, its ECG characteristics, clinical presentation, and management. The paper concludes with a comprehensive review of the electrophysiological mechanisms of torsade de pointes.
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Affiliation(s)
- Nabil El-Sherif
- SUNY Downstate Medical CenterNY, US
- VA NY Harbor Healthcare SystemNY, US
| | - Gioia Turitto
- Weill Cornell Medical College, NewYork-Presbyterian Brooklyn Methodist HospitalNY, US
| | - Mohamed Boutjdir
- SUNY Downstate Medical CenterNY, US
- VA NY Harbor Healthcare SystemNY, US
- NYU School of MedicineNew York NY, US
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50
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Giudicessi JR, Roden DM, Wilde AAM, Ackerman MJ. Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing. Circulation 2019; 137:619-630. [PMID: 29431662 DOI: 10.1161/circulationaha.117.030142] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The acquired and congenital forms of long QT syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, (2) underlies acquired/congenital long QT syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital long QT syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired long QT syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient's genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues.
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Affiliation(s)
- John R Giudicessi
- Departments of Cardiovascular Medicine and Internal Medicine, Clinician-Investigator Training Program, Mayo Clinic, Rochester, MN (J.R.G)
| | - Dan M Roden
- Departments of Biomedical Informatics, Medicine, and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (D.M.R.)
| | - Arthur A M Wilde
- Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, The Netherlands (A.A.M.W.)
| | - Michael J Ackerman
- Departments of Cardiovascular Diseases, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN (M.J.A.)
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