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Drew DA, Kim AE, Lin Y, Qu C, Morrison J, Lewinger JP, Kawaguchi E, Wang J, Fu Y, Zemlianskaia N, Díez-Obrero V, Bien SA, Dimou N, Albanes D, Baurley JW, Wu AH, Buchanan DD, Potter JD, Prentice RL, Harlid S, Arndt V, Barry EL, Berndt SI, Bouras E, Brenner H, Budiarto A, Burnett-Hartman A, Campbell PT, Carreras-Torres R, Casey G, Chang-Claude J, Conti DV, Devall MA, Figueiredo JC, Gruber SB, Gsur A, Gunter MJ, Harrison TA, Hidaka A, Hoffmeister M, Huyghe JR, Jenkins MA, Jordahl KM, Kundaje A, Le Marchand L, Li L, Lynch BM, Murphy N, Nassir R, Newcomb PA, Newton CC, Obón-Santacana M, Ogino S, Ose J, Pai RK, Palmer JR, Papadimitriou N, Pardamean B, Pellatt AJ, Peoples AR, Platz EA, Rennert G, Ruiz-Narvaez E, Sakoda LC, Scacheri PC, Schmit SL, Schoen RE, Stern MC, Su YR, Thomas DC, Tian Y, Tsilidis KK, Ulrich CM, Um CY, van Duijnhoven FJ, Van Guelpen B, White E, Hsu L, Moreno V, Peters U, Chan AT, Gauderman WJ. Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer. SCIENCE ADVANCES 2024; 10:eadk3121. [PMID: 38809988 PMCID: PMC11135391 DOI: 10.1126/sciadv.adk3121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 04/26/2024] [Indexed: 05/31/2024]
Abstract
Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
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Affiliation(s)
- David A. Drew
- Clinical & Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Andre E. Kim
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - John Morrison
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Juan Pablo Lewinger
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Eric Kawaguchi
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jun Wang
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Yubo Fu
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Natalia Zemlianskaia
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Virginia Díez-Obrero
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Stephanie A. Bien
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Niki Dimou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - James W. Baurley
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
- BioRealm LLC, Walnut, CA, USA
| | - Anna H. Wu
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Daniel D. Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia
- Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - John D. Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Research Centre for Hauora and Health, Massey University, Wellington, New Zealand
| | - Ross L. Prentice
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Elizabeth L. Barry
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Emmanouil Bouras
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Arif Budiarto
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | | | - Peter T. Campbell
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Robert Carreras-Torres
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, 17190 Girona, Spain
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany
| | - David V. Conti
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Matthew A.M. Devall
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
| | - Jane C. Figueiredo
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Stephen B. Gruber
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA
- Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA
| | - Andrea Gsur
- Center for Cancer Research, Medical University Vienna, Vienna, Austria
| | - Marc J. Gunter
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK
| | - Tabitha A. Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Akihisa Hidaka
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jeroen R. Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Mark A. Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Kristina M. Jordahl
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Anshul Kundaje
- Department of Genetics, Stanford University, Stanford, CA, USA
- Department of Computer Science, Stanford University, Stanford, CA, USA
| | | | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
- UVA Comprehensive Cancer Center, Charlottesville, VA, USA
| | - Brigid M. Lynch
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Rami Nassir
- Department of Pathology, School of Medicine, Umm Al-Qura’a University, Mecca, Saudi Arabia
| | - Polly A. Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- School of Public Health, University of Washington, Seattle, WA, USA
| | | | - Mireia Obón-Santacana
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
| | - Shuji Ogino
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Jennifer Ose
- Huntsman Cancer Institute, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Rish K. Pai
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Julie R. Palmer
- Slone Epidemiology Center at Boston University, Boston, MA, USA
| | - Nikos Papadimitriou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Bens Pardamean
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | - Andrew J. Pellatt
- Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anita R. Peoples
- Huntsman Cancer Institute, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Elizabeth A. Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
| | - Edward Ruiz-Narvaez
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Lori C. Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Peter C. Scacheri
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Stephanie L. Schmit
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
- Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - Robert E. Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Mariana C. Stern
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Yu-Ru Su
- Biostatistics Division, Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
| | - Duncan C. Thomas
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yu Tian
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- School of Public Health, Capital Medical University, Beijing, China
| | - Konstantinos K. Tsilidis
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Cornelia M. Ulrich
- Huntsman Cancer Institute, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Caroline Y. Um
- Department of Population Science, American Cancer Society, Atlanta, GA, USA
| | | | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Victor Moreno
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L’Hospitalet de Llobregat, 08908 Barcelona, Spain
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Andrew T. Chan
- Clinical & Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - W. James Gauderman
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Zhao Y, Ansarullah, Kumar P, Mahoney JM, He H, Baker C, George J, Li S. Causal network perturbation analysis identifies known and novel type-2 diabetes driver genes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.22.595431. [PMID: 38826370 PMCID: PMC11142180 DOI: 10.1101/2024.05.22.595431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
The molecular pathogenesis of diabetes is multifactorial, involving genetic predisposition and environmental factors that are not yet fully understood. However, pancreatic β-cell failure remains among the primary reasons underlying the progression of type-2 diabetes (T2D) making targeting β-cell dysfunction an attractive pathway for diabetes treatment. To identify genetic contributors to β-cell dysfunction, we investigated single-cell gene expression changes in β-cells from healthy (C57BL/6J) and diabetic (NZO/HlLtJ) mice fed with normal or high-fat, high-sugar diet (HFHS). Our study presents an innovative integration of the causal network perturbation assessment (ssNPA) framework with meta-cell transcriptome analysis to explore the genetic underpinnings of type-2 diabetes (T2D). By generating a reference causal network and in silico perturbation, we identified novel genes implicated in T2D and validated our candidates using the Knockout Mouse Phenotyping (KOMP) Project database.
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Affiliation(s)
- Yue Zhao
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Ansarullah
- Center for Biometric Analysis, The Jackson Laboratory, Bar Harbor, ME, USA
| | - Parveen Kumar
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | | | - Hao He
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Candice Baker
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Joshy George
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Sheng Li
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT, USA
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Efe O, So PNH, Anandh U, Lerma EV, Wiegley N. An Updated Review of Membranous Nephropathy. Indian J Nephrol 2024; 34:105-118. [PMID: 38681023 PMCID: PMC11044666 DOI: 10.25259/ijn_317_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 01/16/2024] [Indexed: 05/01/2024] Open
Abstract
Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. The discovery of phospholipase A2 receptor (PLA2R) as a target antigen has led to a paradigm shift in the understanding and management of MN. At present, serum PLA2R antibodies are used for diagnosis, prognostication, and guiding treatment. Now, with the discovery of more than 20 novel target antigens, antigen mapping is almost complete. The clinical association of certain antigens provides clues for clinicians, such as the association of nerve epidermal growth factor-like 1 with malignancies and indigenous medicines. Serum antibodies are detected for most target antigens, except exostosin 1 and 2 and transforming growth factor-beta receptor 3, but their clinical utility is yet to be defined. Genome-wide association studies and studies investigating environmental factors, such as air pollution, shed more light on the underpinnings of MN. The standard therapy of MN diversified from cyclical cyclophosphamide and steroids to include rituximab and calcineurin inhibitors over the past decades. Here, we provide a cutting-edge review of MN, focusing on genetics, immune system and environmental factors, novel target antigens and their clinical characteristics, and currently available and emerging novel therapies in MN.
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Affiliation(s)
- Orhan Efe
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital; Harvard Medical School, Boston, USA
| | | | - Urmila Anandh
- Department of Nephrology, Amrita Hospitals, Faridabad, Delhi, NCR, India
| | - Edgar V. Lerma
- Department of Medicine, University of Illinois at Chicago; Advocate Christ Medical Center, Oak Lawn, Illinois, USA
| | - Nasim Wiegley
- Division of Nephrology, Department of Medicine, University of California Davis School of Medicine, Sacramento, CA, USA
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Lee SH, Lee CJ, Kang Y, Park JM, Lee JH. A randomized trial of genotype-guided perindopril use. J Hypertens 2023; 41:1768-1774. [PMID: 37602458 DOI: 10.1097/hjh.0000000000003536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2023]
Abstract
OBJECTIVE Cough caused by angiotensin-converting enzyme inhibitors (ACEIs) limits their clinical application and cardiovascular benefits. This randomized trial investigated whether genotype-guided perindopril use could reduce drug-related cough in 20 to 79-year-old individuals with hypertension. METHODS After screening 120 patients and randomization, 68 were assigned to genotyping ( n = 41) and control ( n = 27) groups. NELL1 p.Arg382Trp (rs8176786) and intron (rs10766756) genotype information was used to subdivide the genotyping group into high-risk and low-risk subgroups with at least one or no risk alleles for ACEI-related cough, respectively. The high-risk subgroup received candesartan (8 mg/day) for 6 weeks, whereas the low-risk subgroup received perindopril (4 mg/day). The control group, which was not genotyped, received perindopril (4 mg/day). The primary outcome variables were cough and moderate/severe cough; the secondary outcome variable was any adverse event. RESULTS During the 6-week period, the risk of cough was lower in the genotyping group than in the control group [five (12.2%) and nine (33.3%) participants, respectively; hazard ratio: 0.25; log-rank P = 0.017]. The moderate/severe cough risk was also lower in the genotyping group [one (2.4%) and five (18.5%) participants, respectively; hazard ratio: 0.12; log-rank P = 0.025]. Differences in cough (hazard ratio: 0.56; log-rank P = 0.32) and moderate/severe cough risk (hazard ratio: 0.26; log-rank P = 0.19) between the low-risk and control groups were not significant. The risk of total adverse events was similar between any two groups. CONCLUSION Cough risk was lower during genotype-guided treatment than during conventional treatment. These results support the utility of NELL1 variant data in clinical decision making to personalize renin-angiotensin system blocker therapy use. TRIAL REGISTRATION ClinicalTrials.gov number: NCT05535595 (retrospectively registered at September 7, 2022).
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Affiliation(s)
- Sang-Hak Lee
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine
| | - Chan Joo Lee
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine
| | - Yura Kang
- Department of Biostatistics and Computing, Graduate School, Yonsei University, Seoul
| | - Jung Mi Park
- Health Insurance Review & Assessment Service, Wonju
| | - Ji Hyun Lee
- Department of Pharmacology and Therapeutics, Kyung Hee University College of Medicine
- Department of Biomedical Science and Technology, Kyung Hee University, Seoul, Korea
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Vemuri K, Radi SH, Sladek FM, Verzi MP. Multiple roles and regulatory mechanisms of the transcription factor HNF4 in the intestine. Front Endocrinol (Lausanne) 2023; 14:1232569. [PMID: 37635981 PMCID: PMC10450339 DOI: 10.3389/fendo.2023.1232569] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 07/24/2023] [Indexed: 08/29/2023] Open
Abstract
Hepatocyte nuclear factor 4-alpha (HNF4α) drives a complex array of transcriptional programs across multiple organs. Beyond its previously documented function in the liver, HNF4α has crucial roles in the kidney, intestine, and pancreas. In the intestine, a multitude of functions have been attributed to HNF4 and its accessory transcription factors, including but not limited to, intestinal maturation, differentiation, regeneration, and stem cell renewal. Functional redundancy between HNF4α and its intestine-restricted paralog HNF4γ, and co-regulation with other transcription factors drive these functions. Dysregulated expression of HNF4 results in a wide range of disease manifestations, including the development of a chronic inflammatory state in the intestine. In this review, we focus on the multiple molecular mechanisms of HNF4 in the intestine and explore translational opportunities. We aim to introduce new perspectives in understanding intestinal genetics and the complexity of gastrointestinal disorders through the lens of HNF4 transcription factors.
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Affiliation(s)
- Kiranmayi Vemuri
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, United States
- Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States
| | - Sarah H. Radi
- Department of Molecular, Cell and Systems Biology, University of California, Riverside, Riverside, CA, United States
- Department of Biochemistry, University of California, Riverside, Riverside, CA, United States
| | - Frances M. Sladek
- Department of Molecular, Cell and Systems Biology, University of California, Riverside, Riverside, CA, United States
| | - Michael P. Verzi
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, United States
- Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States
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Markelova M, Senina A, Khusnutdinova D, Siniagina M, Kupriyanova E, Shakirova G, Odintsova A, Abdulkhakov R, Kolesnikova I, Shagaleeva O, Lyamina S, Abdulkhakov S, Zakharzhevskaya N, Grigoryeva T. Association between Taxonomic Composition of Gut Microbiota and Host Single Nucleotide Polymorphisms in Crohn's Disease Patients from Russia. Int J Mol Sci 2023; 24:ijms24097998. [PMID: 37175705 PMCID: PMC10178390 DOI: 10.3390/ijms24097998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 04/25/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Crohn's disease (CD) is a chronic relapsing inflammatory bowel disease of unknown etiology. Genetic predisposition and dysbiotic gut microbiota are important factors in the pathogenesis of CD. In this study, we analyzed the taxonomic composition of the gut microbiota and genotypes of 24 single nucleotide polymorphisms (SNP) associated with the risk of CD. The studied cohorts included 96 CD patients and 24 healthy volunteers from Russia. Statistically significant differences were found in the allele frequencies for 8 SNPs and taxonomic composition of the gut microbiota in CD patients compared with controls. In addition, two types of gut microbiota communities were identified in CD patients. The main distinguishing driver of bacterial families for the first community type are Bacteroidaceae and unclassified members of the Clostridiales order, and the second type is characterized by increased abundance of Streptococcaceae and Enterobacteriaceae. Differences in the allele frequencies of the rs9858542 (BSN), rs3816769 (STAT3), and rs1793004 (NELL1) were also found between groups of CD patients with different types of microbiota communities. These findings confirm the complex multifactorial nature of CD.
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Affiliation(s)
- Maria Markelova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Anastasia Senina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Dilyara Khusnutdinova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Maria Siniagina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Elena Kupriyanova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | | | | | - Rustam Abdulkhakov
- Hospital Therapy Department, Kazan State Medical University, 420012 Kazan, Russia
| | - Irina Kolesnikova
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Olga Shagaleeva
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Svetlana Lyamina
- Molecular Pathology of Digestion Laboratory, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, 127473 Moscow, Russia
| | - Sayar Abdulkhakov
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Natalia Zakharzhevskaya
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Tatiana Grigoryeva
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
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Kern I, Schoffer O, Richter T, Kiess W, Flemming G, Winkler U, Quietzsch J, Wenzel O, Zurek M, Manuwald U, Hegewald J, Li S, Weidner J, de Laffolie J, Zimmer KP, Kugler J, Laass MW, Rothe U. Current and projected incidence trends of pediatric-onset inflammatory bowel disease in Germany based on the Saxon Pediatric IBD Registry 2000–2014 –a 15-year evaluation of trends. PLoS One 2022; 17:e0274117. [PMID: 36084003 PMCID: PMC9462751 DOI: 10.1371/journal.pone.0274117] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 08/23/2022] [Indexed: 11/19/2022] Open
Abstract
Aims
An increasing number of children and adolescents worldwide suffer from inflammatory bowel disease (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC). The present work aims to investigate the incidence, prevalence and future trends of IBD in children and adolescents in Saxony, Germany.
Methods
The Saxon Pediatric IBD Registry collected data on patients up to 15 years of age from all 31 pediatric hospitals and pediatric gastroenterologists in Saxony over a 15-year period (2000–2014). In 2019, an independent survey estimated a registry completeness of 95.7%. Age-standardized incidence rates (ASR) per 100,000 person-years (PY) and prevalence per 100,000 children and adolescents were calculated. Evaluation was also been performed in sex and age subgroups. Joinpoint and Poisson regression were used for trend analyses and projections.
Results
532 patients with confirmed IBD during 2000–2014 were included in the epidemiological evaluation. 63.5% (n = 338) patients had CD, 33.1% (n = 176) had UC and 3.4% (n = 18) had unclassified IBD (IBD-U). The 15-year IBD prevalence was 111.8 [95%-CI: 102.3–121.3] per 100,000. The incidence ASR of IBD per 100,000 PY over the whole observation period was 7.5 [6.9–8.1]. ASR for the subtypes were 4.8 [4.3–5.3] for CD, 2.5 [2.1–2.9] for UC and 0.3 [0.1–0.4] for IBD-U. The trend analysis of ASR using the joinpoint regression confirmed a significant increase for incidence of IBD as well as CD. For IBD, the ASR per 100,000 PY increased from 4.6 [2.8–6.3] in 2000 to 8.2 [7.5–13.6] in 2014; projected incidence rates for IBD in Germany are 12.9 [6.5–25.5] in the year 2025 and 14.9 [6.7–32.8] in 2030, respectively. Thus, the number of new IBD diagnoses in Germany would more than triple (325%) in 2030 compared to 2000. The increase is expected to be faster in CD than UC, and be more in males than in females. The expected number of newly diagnosed children with IBD in Germany is projected to rise to about 1,584 [1,512–1,655] in 2025, and to about 1,918 [1,807–2,29] in 2030.
Conclusion
The incidence of IBD in children and adolescents in Saxony increased at a similar rate as in other developed countries during the observation period. Given this trend, the health care system must provide adequate resources for the care of these young patients in the future.
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Affiliation(s)
- Ivana Kern
- Department of Health Sciences/Public Health, Institute and Policlinic for Occupational and Social Medicine, Faculty of Medicine „Carl Gustav Carus”, TU Dresden, Dresden, Germany
- * E-mail:
| | - Olaf Schoffer
- Center for Evidence-based Healthcare, University Hospital and Faculty of Medicine “Carl Gustav Carus”, TU Dresden, Dresden, Germany
| | - Thomas Richter
- Clinic for Children and Adolescents, Hospital St. Georg, Leipzig, Germany
| | - Wieland Kiess
- Center for Pediatric Research, Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
| | - Gunter Flemming
- Center for Pediatric Research, Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
| | - Ulf Winkler
- Clinic for Children and Adolescents, Hospital Bautzen, Oberlausitz-Hospitals, Bautzen, Germany
| | - Jürgen Quietzsch
- Clinic for Children and Adolescents, DRK Hospital Lichtenstein, Lichtenstein, Germany
| | - Olaf Wenzel
- Clinic for Children and Adolescents, Helios Hospital Aue, Bad Schlema, Germany
| | - Marlen Zurek
- Clinic for Children and Adolescents, Hospital St. Georg, Leipzig, Germany
| | - Ulf Manuwald
- Department of Health Sciences/Public Health, Institute and Policlinic for Occupational and Social Medicine, Faculty of Medicine „Carl Gustav Carus”, TU Dresden, Dresden, Germany
| | - Janice Hegewald
- Department of Occupational, Social and Environmental Epidemiology, Institute and Policlinic for Occupational and Social Medicine, Faculty of Medicine „Carl Gustav Carus”, TU Dresden, Dresden, Germany
| | - Shi Li
- Department of Health Sciences/Public Health, Institute and Policlinic for Occupational and Social Medicine, Faculty of Medicine „Carl Gustav Carus”, TU Dresden, Dresden, Germany
| | - Jens Weidner
- Center for Medical Informatics, Institute for Medical Informatics and Biometry, Faculty of Medicine “Carl Gustav Carus”, TU Dresden, Dresden, Germany
| | - Jan de Laffolie
- Department of General Pediatrics, Children’s Gastroenterology/ Hepatology/ Nutrition, Justus-Liebig-University Gießen, CEDATA-GPGE Working Group, Gießen, Germany
| | - Klaus-Peter Zimmer
- Department of General Pediatrics, Children’s Gastroenterology/ Hepatology/ Nutrition, Justus-Liebig-University Gießen, CEDATA-GPGE Working Group, Gießen, Germany
| | - Joachim Kugler
- Department of Health Sciences/Public Health, Institute and Policlinic for Occupational and Social Medicine, Faculty of Medicine „Carl Gustav Carus”, TU Dresden, Dresden, Germany
| | - Martin W. Laass
- University Hospital for Children and Adolescents, Faculty of Medicine “Carl Gustav Carus”, TU Dresden, Dresden, Germany
| | - Ulrike Rothe
- Department of Health Sciences/Public Health, Institute and Policlinic for Occupational and Social Medicine, Faculty of Medicine „Carl Gustav Carus”, TU Dresden, Dresden, Germany
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8
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Duan C, Townley HE. Isolation of NELL 1 Aptamers for Rhabdomyosarcoma Targeting. Bioengineering (Basel) 2022; 9:bioengineering9040174. [PMID: 35447734 PMCID: PMC9032205 DOI: 10.3390/bioengineering9040174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/06/2022] [Accepted: 04/13/2022] [Indexed: 12/13/2022] Open
Abstract
NELL1 (Neural epidermal growth factor-like (EGFL)-like protein) is an important biomarker associated with tissue and bone development and regeneration. NELL1 upregulation has been linked with metastasis and negative prognosis in rhabdomyosarcoma (RMS). Furthermore, multiple recent studies have also shown the importance of NELL1 in inflammatory bowel disease and membranous nephropathy, amongst other diseases. In this study, several anti-NELL1 DNA aptamers were selected from a randomized ssDNA pool using a fluorescence-guided method and evaluated for their binding affinity and selectivity. Several other methods such as a metabolic assay and confocal microscopy were also applied for the evaluation of the selected aptamers. The top three candidates were evaluated further, and AptNCan3 was shown to have a binding affinity up to 959.2 nM. Selectivity was examined in the RH30 RMS cells that overexpressed NELL1. Both AptNCan2 and AptNCan3 could significantly suppress metabolic activity in RMS cells. AptNCan3 was found to locate on the cell membrane and also on intracellular vesicles, which matched the location of NELL1 shown by antibodies in previous research. These results indicate that the selected anti-NELL1 aptamer showed strong and highly specific binding to NELL1 and therefore has potential to be used for in vitro or in vivo studies and treatments.
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Affiliation(s)
- Chengchen Duan
- Nuffield Department of Women’s and Reproductive Health, Oxford University John Radcliffe Hospital, Oxford OX3 9DU, UK;
| | - Helen Elizabeth Townley
- Nuffield Department of Women’s and Reproductive Health, Oxford University John Radcliffe Hospital, Oxford OX3 9DU, UK;
- Department of Engineering Science, Oxford University, Oxford OX1 3PJ, UK
- Correspondence: ; Tel.: +44-1865-283792
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9
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A potent HNF4α agonist reveals that HNF4α controls genes important in inflammatory bowel disease and Paneth cells. PLoS One 2022; 17:e0266066. [PMID: 35385524 PMCID: PMC8985954 DOI: 10.1371/journal.pone.0266066] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 03/11/2022] [Indexed: 11/19/2022] Open
Abstract
HNF4α has been implicated in IBD through a number of genome-wide association studies. Recently, we developed potent HNF4α agonists, including N-trans caffeoyltyramine (NCT). NCT was identified by structural similarity to previously the previously identified but weak HNF4α agonists alverine and benfluorex. Here, we administered NCT to mice fed a high fat diet, with the goal of studying the role of HNF4α in obesity-related diseases. Intestines from NCT-treated mice were examined by RNA-seq to determine the role of HNF4α in that organ. Surprisingly, the major classes of genes altered by HNF4α were involved in IBD and Paneth cell biology. Multiple genes downregulated in IBD were induced by NCT. Paneth cells identified by lysozyme expression were reduced in high fat fed mice. NCT reversed the effect of high fat diet on Paneth cells, with multiple markers being induced, including a number of defensins, which are critical for Paneth cell function and intestinal barrier integrity. NCT upregulated genes that play important role in IBD and that are downregulated in that disease. It reversed the loss of Paneth cell markers that occurred in high fat diet fed mice. These data suggest that HNF4α could be a therapeutic target for IBD and that the agonists that we have identified could be candidate therapeutics.
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10
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Lee CJ, Choi B, Pak H, Park JM, Lee JH, Lee SH. Genetic Variants Associated with Adverse Events after Angiotensin-Converting Enzyme Inhibitor Use: Replication after GWAS-Based Discovery. Yonsei Med J 2022; 63:342-348. [PMID: 35352885 PMCID: PMC8965428 DOI: 10.3349/ymj.2022.63.4.342] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/13/2021] [Accepted: 01/11/2022] [Indexed: 11/27/2022] Open
Abstract
PURPOSE Angiotensin-converting enzyme inhibitors (ACEIs) are medications generally prescribed for patients with high cardiovascular risk; however, they are suboptimally used due to frequent adverse events (AEs). The present study aimed to identify and replicate the genetic variants associated with ACEI-related AEs in the Korean population. MATERIALS AND METHODS A two-stage approach employing genome-wide association study (GWAS)-based discovery and replication through target sequencing was used. In total, 1300 individuals received ACEIs from 2001 to 2007; among these, 228 were selected for GWAS. An additional 336 patients were selected for replication after screening 1186 subjects treated from 2008 to 2018. Candidate genes for target sequencing were selected based on the present GWAS, previous GWASs, and data from the PharmGKB database. Furthermore, association analyses were performed between no AE and AE or cough groups after target sequencing. RESULTS Five genes, namely CRIM1, NELL1, CACNA1D, VOPP1, and MYBPC1, were identified near variants associated with ACEI-related AEs. During target sequencing of 34 candidate genes, six single-nucleotide polymorphisms (SNPs; rs5224, rs8176786, rs10766756, rs561868018, rs4974539, and rs10946364) were replicated for association with all ACEI-related AEs. Four of these SNPs and rs147912715 exhibited associations with ACEI-related cough, whereas four SNPs (rs5224, rs81767786, rs10766756, and rs4974539 near BDKRB2, NELL1, NELL1 intron, and CPN2, respectively) were significantly associated with both categories of AEs. CONCLUSION Several variants, including novel and known variants, were successfully replicated and found to have associations with ACEI-related AEs. These results provide rare and clinically relevant information for safer use of ACEIs.
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Affiliation(s)
- Chan Joo Lee
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Bogeum Choi
- Kyung Hee University College of Medicine, Seoul, Korea
| | - Hayeon Pak
- Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Korea
| | - Jung Mi Park
- Department of Biostatistics and Computing, Graduate School, Yonsei University, Seoul, Korea
| | - Ji Hyun Lee
- Department of Clinical Pharmacology and Therapeutics, Kyung Hee University College of Medicine, Seoul, Korea
- Department of Biomedical Science and Technology, Kyung Hee University, Seoul, Korea.
| | - Sang-Hak Lee
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
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11
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Cheng X, Shi J, Jia Z, Ha P, Soo C, Ting K, James AW, Shi B, Zhang X. NELL-1 in Genome-Wide Association Studies across Human Diseases. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:395-405. [PMID: 34890556 PMCID: PMC8895422 DOI: 10.1016/j.ajpath.2021.11.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 11/19/2021] [Accepted: 11/24/2021] [Indexed: 02/08/2023]
Abstract
Neural epidermal growth factor-like (EGFL)-like protein (NELL)-1 is a potent and key osteogenic factor in the development and regeneration of skeletal tissues. Intriguingly, accumulative data from genome-wide association studies (GWASs) have started unveiling potential broader roles of NELL-1 beyond its functions in bone and cartilage. With exploration of the genetic variants of the entire genome in large-scale disease cohorts, GWASs have been used for establishing the connection between specific single-nucleotide polymorphisms of NELL1, in addition to osteoporosis, metabolic diseases, inflammatory conditions, neuropsychiatric diseases, neurodegenerative disorders, and malignant tumors. This review summarizes the findings from GWASs on the manifestation, significance level, implications on function, and correlation of specific NELL1 single-nucleotide polymorphisms in various disorders in humans. By offering a unique and comprehensive correlation between genetic variants and plausible functions of NELL1 in GWASs, this review illustrates the wide range of potential effects of a single gene on the pathogenesis of multiple disorders in humans.
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Affiliation(s)
- Xu Cheng
- State Key Laboratory of Oral Diseases, National Clinical Research Centre for Oral Diseases, and the Department of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California-Los Angeles, Los Angeles, California
| | - Jiayu Shi
- Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California-Los Angeles, Los Angeles, California
| | - Zhonglin Jia
- State Key Laboratory of Oral Diseases, National Clinical Research Centre for Oral Diseases, and the Department of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Pin Ha
- Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California-Los Angeles, Los Angeles, California
| | - Chia Soo
- Division of Plastic and Reconstructive Surgery, Department of Orthopaedic Surgery, Orthopaedic Hospital Research Center, University of California-Los Angeles, Los Angeles, California
| | - Kang Ting
- Forsyth Institute, affiliate of the Harvard School of Dental Medicine, Boston, Massachusetts
| | - Aaron W James
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Bing Shi
- State Key Laboratory of Oral Diseases, National Clinical Research Centre for Oral Diseases, and the Department of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
| | - Xinli Zhang
- Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California-Los Angeles, Los Angeles, California.
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12
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Transcriptional programmes underlying cellular identity and microbial responsiveness in the intestinal epithelium. Nat Rev Gastroenterol Hepatol 2021; 18:7-23. [PMID: 33024279 PMCID: PMC7997278 DOI: 10.1038/s41575-020-00357-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/12/2020] [Indexed: 12/19/2022]
Abstract
The intestinal epithelium serves the unique and critical function of harvesting dietary nutrients, while simultaneously acting as a cellular barrier separating tissues from the luminal environment and gut microbial ecosystem. Two salient features of the intestinal epithelium enable it to perform these complex functions. First, cells within the intestinal epithelium achieve a wide range of specialized identities, including different cell types and distinct anterior-posterior patterning along the intestine. Second, intestinal epithelial cells are sensitive and responsive to the dynamic milieu of dietary nutrients, xenobiotics and microorganisms encountered in the intestinal luminal environment. These diverse identities and responsiveness of intestinal epithelial cells are achieved in part through the differential transcription of genes encoded in their shared genome. Here, we review insights from mice and other vertebrate models into the transcriptional regulatory mechanisms underlying intestinal epithelial identity and microbial responsiveness, including DNA methylation, chromatin accessibility, histone modifications and transcription factors. These studies are revealing that most transcription factors involved in intestinal epithelial identity also respond to changes in the microbiota, raising both opportunities and challenges to discern the underlying integrative transcriptional regulatory networks.
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13
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Caza TN, Hassen SI, Dvanajscak Z, Kuperman M, Edmondson R, Herzog C, Storey A, Arthur J, Cossey LN, Sharma SG, Kenan DJ, Larsen CP. NELL1 is a target antigen in malignancy-associated membranous nephropathy. Kidney Int 2020; 99:967-976. [PMID: 32828756 DOI: 10.1016/j.kint.2020.07.039] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 07/02/2020] [Accepted: 07/09/2020] [Indexed: 12/13/2022]
Abstract
Patients with membranous nephropathy have an increased risk of malignancy compared to the general population, but the target antigen for malignancy-associated membranous nephropathy is unknown. To explore this, we utilized mass spectrometry for antigen discovery in malignancy-associated membranous nephropathy examining immune complexes eluted from frozen kidney biopsy tissue using protein G bead immunoglobulin capture. Antigen discovery was performed comparing cases of membranous nephropathy of unknown and known type. Mass spectrophotometric analysis revealed that nerve epidermal growth factor-like 1 (NELL1) immune complexes were uniquely present within the biopsy tissue in membranous nephropathy. Additional NELL1-positive cases were subsequently identified by immunofluorescence. In a consecutive series, 3.8% of PLA2R- and THSD7A-negative cases were NELL1-positive. These NELL1-positive cases had segmental to incomplete IgG capillary loop staining (93.4%) and dominant or co-dominant IgG1-subclass staining (95.5%). The mean age of patients with NELL1-positive membranous nephropathy was 66.8 years, with a slight male predominance (58.2%) and 33% had concurrent malignancy. Compared with PLA2R- and THSD7A-positive cases of membranous nephropathy, there was a greater proportion of cases with malignancies in the NELL1-associated group. Thus, NELL1-associated membranous nephropathy has a unique histopathology characterized by incomplete capillary loop staining, IgG1-predominance, and is more often associated with malignancy than other known types of membranous nephropathy.
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Affiliation(s)
| | | | | | | | - Rick Edmondson
- University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Christian Herzog
- University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Aaron Storey
- University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - John Arthur
- University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
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14
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Li C, Zhang X, Zheng Z, Nguyen A, Ting K, Soo C. Nell-1 Is a Key Functional Modulator in Osteochondrogenesis and Beyond. J Dent Res 2019; 98:1458-1468. [PMID: 31610747 DOI: 10.1177/0022034519882000] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Neural EGFL-like 1 (Nell-1) is a well-studied osteogenic factor that has comparable osteogenic potency with the Food and Drug Administration-approved bone morphogenic protein 2 (BMP-2). In this review, which aims to summarize the advanced Nell-1 research in the past 10 y, we start with the correlation of structural and functional relevance of the Nell-1 protein with the identification of a specific receptor of Nell-1, contactin-associated protein-like 4 (Cntnap4), for osteogenesis. The indispensable role of Nell-1 in normal craniofacial and appendicular skeletal development and growth was also defined by using the newly developed tissue-specific Nell-1 knockout mouse lines in addition to the existing transgenic mouse models. With the achievements on Nell-1's osteogenic therapeutic evaluations from multiple preclinical animal models for local and systemic bone regeneration, the synergistic effect of Nell-1 with BMP-2 on osteogenesis, as well as the advantages of Nell-1 as an osteogenic protein with antiadipogenic, anti-inflammatory, and provascularized characteristics over BMP-2 in bone tissue engineering, is highlighted, which lays the groundwork for the clinical trial approval of Nell-1. At the molecular level, besides the mitogen-activated protein kinase (MAPK) signaling pathway, we emphasize the significant involvement of the Wnt/β-catenin pathway as well as the key regulatory molecules Runt-related transcription factor 2 (Runx2) in Nell-1-induced osteogenesis. In addition, the involvement of Nell-1 in chondrogenesis and its relevant pathologies have been revealed with the participation of the nuclear factor of activated T cells 1 (Nfatc1), Runx3, and Indian hedgehog (Ihh) signaling pathways, although the mechanistic insights of Nell-1's osteochondrogenic property will be continuously evolving. With this perspective, we elucidate some emerging and novel functional properties of Nell-1 in oral-dental and neural tissues that will be the frontiers of future Nell-1 studies beyond the context of bone and cartilage. As such, the therapeutic potential of Nell-1 continues to evolve and grow with continuous pursuit.
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Affiliation(s)
- C Li
- Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA
| | - X Zhang
- Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA
| | - Z Zheng
- Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA
| | - A Nguyen
- Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA
| | - K Ting
- Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA
| | - C Soo
- Division of Plastic and Reconstructive Surgery, Department of Orthopaedic Surgery, Orthopaedic Hospital Research Center, University of California, Los Angeles, CA, USA
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15
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Chandra N, Srivastava A, Kumar S. Bacterial biofilms in human gastrointestinal tract: An intricate balance between health and inflammatory bowel diseases. World J Pharmacol 2019; 8:26-40. [DOI: 10.5497/wjp.v8.i3.26] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 07/05/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023] Open
Affiliation(s)
- Niharika Chandra
- Faculty of Biotechnology, Institute of Bio-Sciences and Technology, Shri Ramswaroop Memorial University, Uttar Pradesh 225003, India
| | - Ankita Srivastava
- Faculty of Bio-Sciences, Institute of Bio-Sciences and Technology, Shri Ramswaroop Memorial University, Uttar Pradesh 225003, India
| | - Sunil Kumar
- Faculty of Bio-Sciences, Institute of Bio-Sciences and Technology, Shri Ramswaroop Memorial University, Uttar Pradesh 225003, India
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16
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Yeh MM, Bosch DE, Daoud SS. Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases. World J Gastroenterol 2019; 25:4074-4091. [PMID: 31435165 PMCID: PMC6700705 DOI: 10.3748/wjg.v25.i30.4074] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 07/15/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocyte nuclear factor 4-alpha (HNF4α) is a highly conserved member of nuclear receptor superfamily of ligand-dependent transcription factors that is expressed in liver and gastrointestinal organs (pancreas, stomach, and intestine). In liver, HNF4α is best known for its role as a master regulator of liver-specific gene expression and essential for adult and fetal liver function. Dysregulation of HNF4α expression has been associated with many human diseases such as ulcerative colitis, colon cancer, maturity-onset diabetes of the young, liver cirrhosis, and hepatocellular carcinoma. However, the precise role of HNF4α in the etiology of these human pathogenesis is not well understood. Limited information is known about the role of HNF4α isoforms in liver and gastrointestinal disease progression. There is, therefore, a critical need to know how disruption of the expression of these isoforms may impact on disease progression and phenotypes. In this review, we will update our current understanding on the role of HNF4α in human liver and gastrointestinal diseases. We further provide additional information on possible use of HNF4α as a target for potential therapeutic approaches.
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Affiliation(s)
- Matthew M Yeh
- Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Dustin E Bosch
- Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Sayed S Daoud
- Department of Pharmaceutical Sciences, Washington State University Health Sciences, Spokane, WA 99210, United States
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17
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Li Z, Wang Y, Zhu Y. Association of miRNA-146a rs2910164 and miRNA-196 rs11614913 polymorphisms in patients with ulcerative colitis: A meta-analysis and review. Medicine (Baltimore) 2018; 97:e12294. [PMID: 30278502 PMCID: PMC6181578 DOI: 10.1097/md.0000000000012294] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND It has been reported that the single nucleotide polymorphisms (SNPs) miRNA-196 (miR-196) rs11614913 and miRNA-146a (miR-146a) rs2910164 are related to susceptibility to ulcerative colitis (UC). Because the previously reported results have been mixed and uncertain, the aim of this study was to perform a meta-analysis and review to assess the relationship between these 2 SNPs and UC risk. METHODS In this analysis, 5 studies involving 1023 cases and 1769 controls for miR-196 rs11614913 and 4 studies involving 827 cases and 1451 controls for miR-146 rs2910164 were included. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to pool the effect size. RESULTS A decreased risk of UC was identified in homozygote comparison (GG vs CC: OR = 0.69, 95% CI: 0.52-0.93, P = .02), recessive comparison (GG vs CG + CC: OR = 0.74, 95% CI: 0.59-0.92, P = .007), and dominant comparison (GG + CG vs CC: OR = 0.79, 95% CI: 0.65-0.97, P = .02) of miR-146 rs2910164 in Asian but not Caucasian population. No evidence of an association was shown between the rs11614913 polymorphism and UC risk in allelic, heterozygote, homozygote, recessive, and dominant models in both Caucasian and Asian populations (P > .05). CONCLUSIONS MiR-146 rs2910164, but not miR-196 rs11614913, was associated with a decreased risk of UC in Asian population. However, the results should be treated with caution because of the limited sample size and heterogeneity. Well-designed studies with large sample sizes and more ethnic groups are needed to validate the risks identified in the current meta-analysis and review.
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Affiliation(s)
- Zhongyi Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University
| | - Yao Wang
- Department of Epidemiology, Medical School of Jinan University, Guangzhou, Guangdong Province
| | - Yi Zhu
- Department of Gastroenterological Surgery, First Hospital of Jiaxing, Jiaxing, Zhejiang, China
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Reconstructing the Molecular Function of Genetic Variation in Regulatory Networks. Genetics 2017; 207:1699-1709. [PMID: 29046401 DOI: 10.1534/genetics.117.300381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 09/11/2017] [Indexed: 11/18/2022] Open
Abstract
Over the past decade, genetic studies have recognized hundreds of polymorphic DNA loci called response QTLs (reQTLs) as potential contributors to interindividual variation in transcriptional responses to stimulations. Such reQTLs commonly affect the transduction of signals along the regulatory network that controls gene transcription. Identifying the pathways through which reQTLs perturb the underlying network has been a major challenge. Here, we present GEVIN ("Genome-wide Embedding of Variation In Networks"), a methodology that simultaneously identifies a reQTL and the particular pathway in which the reQTL affects downstream signal transduction along the network. Using synthetic data, we show that this algorithm outperforms existing pathway identification and reQTL identification methods. We applied GEVIN to the analysis of murine and human dendritic cells in response to pathogenic components. These analyses revealed significant reQTLs together with their perturbed Toll-like receptor signaling pathways. GEVIN thus offers a powerful framework that renders a comprehensive picture of disease-related DNA loci and their molecular functions within regulatory networks.
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Schieffer KM, Wright JR, Harris LR, Deiling S, Yang Z, Lamendella R, Yochum GS, Koltun WA. NOD2 Genetic Variants Predispose One of Two Familial Adenomatous Polyposis Siblings to Pouchitis Through Microbiome Dysbiosis. J Crohns Colitis 2017; 11. [PMID: 28633443 PMCID: PMC5881696 DOI: 10.1093/ecco-jcc/jjx083] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Individuals with familial adenomatous polyposis (FAP) may undergo a total proctocolectomy with ileal pouch-anal anastomosis (IPAA) to surgically treat their disease. Inflammation of the ileal pouch, termed pouchitis, is uncommon in FAP patients but prevalent in patients who received IPAA for ulcerative colitis, a type of inflammatory bowel disease (IBD). METHODS AND RESULTS We report on two FAP siblings, living in the same household, who underwent IPAA surgery within one week of each other. Their mother also had an IPAA for FAP. One sibling developed pouchitis while his brother and mother have remained pouchitis-free. We investigated the genetic and microbial factors that might explain the development of pouchitis in the one sibling. We surveyed DNA isolated from the two brothers and their parents for NOD2 IBD risk variants by Sanger sequencing. The composition of mucosa-associated bacteria was analyzed by 16S rRNA gene sequencing on terminal ileum and rectal tissue collected at the time of surgical resection from the two brothers. The sibling with pouchitis inherited the IBD-associated risk alleles for NOD2 (rs17221417 and rs2076756) from his healthy father. Both the mother and unaffected brother lacked these variants. Microbiome sequencing of the terminal ileum and rectum found reduced levels of potentially 'beneficial' bacteria (Faecalibacterium prausnitzii, Bacteroides, and Ruminococcaceae) in the sibling with pouchitis relative to his brother. CONCLUSION These findings suggest that the NOD2 signaling pathway may contribute to intrinsic bacterial dysbiosis which is pre-existing and which may then predispose individuals to pouchitis after IPAA surgery.
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Affiliation(s)
- Kathleen M Schieffer
- Department of Surgery, Pennsylvania State University College of Medicine, Hershey, PA
| | - Justin R Wright
- Department of Biology, Juniata College, Huntingdon, PA,Wright Labs, LLC, Huntingdon, PA
| | - Leonard R Harris
- Department of Surgery, Pennsylvania State University College of Medicine, Hershey, PA
| | - Sue Deiling
- Department of Surgery, Pennsylvania State University College of Medicine, Hershey, PA
| | - Zhaohai Yang
- Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA
| | - Regina Lamendella
- Department of Biology, Juniata College, Huntingdon, PA,Wright Labs, LLC, Huntingdon, PA
| | - Gregory S Yochum
- Department of Surgery, Pennsylvania State University College of Medicine, Hershey, PA,Department of Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA
| | - Walter A Koltun
- Department of Surgery, Pennsylvania State University College of Medicine, Hershey, PA,Corresponding Author: Walter A. Koltun, MD, The Pennsylvania State University, College of Medicine, Department of Surgery, Division of Colon and Rectal Surgery, 500 University Drive, Hershey, PA 17033-0850. Tel: 717-531-5164; Fax: 717-531-0646;
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Zhang YM, Zhou XJ, Cheng FJ, Qi YY, Hou P, Zhao MH, Zhang H. Autophagy-related gene LRRK2 is likely a susceptibility gene for systemic lupus erythematosus in northern Han Chinese. Oncotarget 2017; 8:13754-13761. [PMID: 28099919 PMCID: PMC5355135 DOI: 10.18632/oncotarget.14631] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 01/06/2017] [Indexed: 01/24/2023] Open
Abstract
Autophagy is associated with various immune diseases, including systemic lupus erythematosus (SLE). Seven variants within autophagy-related genes previously reported to show top association signals by genome-wide association studies in immune diseases were selected for analysis. Initially, 510 SLE patients (631 controls) were enrolled in the study. An additional independent cohort of 511 SLE patients (687 controls) was included for replication. Polymorphism rs2638272 in LRRK2 gene showed significant association with susceptibility to SLE (P = 1.14 × 10−2) within the initial patient population. This was independently replicated (second patient cohort), and was reinforced with combination (P = 2.82 × 10−3). By combining multiple layers of regulatory effects, rs1491941 in high linkage disequilibrium with rs2638272 (r2 = 0.99) was regarded to have the strongest function in LRRK2. The rs1491941 protective A-allele exhibited an increase of nuclear protein binding, and an increase in LRRK2 transcription compared with G-allele. Furthermore, we observed increased transcription levels of LRRK2 in peripheral blood mononuclear cells from SLE patients compared with controls. In conclusion, we have identified a novel genetic association between the autophagy-related LRRK2 gene and susceptibility to SLE. By integrating layers of functional data, we derived the beneficial effect of autophagy on the pathogenesis of SLE.
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Affiliation(s)
- Yue-Miao Zhang
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China
| | - Xu-Jie Zhou
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China
| | - Fa-Juan Cheng
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China
| | - Yuan-Yuan Qi
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China
| | - Ping Hou
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China
| | - Ming-Hui Zhao
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China
| | - Hong Zhang
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China
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Horak P, Kucerova P, Cervinkova M. Potential markers for early diagnostics of Colorectal cancer and Inflammatory bowel disease in humans : intestinal microorganisms and immune system (teammates or rivals). CANADIAN JOURNAL OF BIOTECHNOLOGY 2017. [DOI: 10.24870/cjb.2017-000109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2022] Open
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22
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Davison JM, Lickwar CR, Song L, Breton G, Crawford GE, Rawls JF. Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha. Genome Res 2017; 27:1195-1206. [PMID: 28385711 PMCID: PMC5495071 DOI: 10.1101/gr.220111.116] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 03/30/2017] [Indexed: 02/07/2023]
Abstract
Microbiota influence diverse aspects of intestinal physiology and disease in part by controlling tissue-specific transcription of host genes. However, host genomic mechanisms mediating microbial control of intestinal gene expression are poorly understood. Hepatocyte nuclear factor 4 (HNF4) is the most ancient family of nuclear receptor transcription factors with important roles in human metabolic and inflammatory bowel diseases, but a role in host response to microbes is unknown. Using an unbiased screening strategy, we found that zebrafish Hnf4a specifically binds and activates a microbiota-suppressed intestinal epithelial transcriptional enhancer. Genetic analysis revealed that zebrafish hnf4a activates nearly half of the genes that are suppressed by microbiota, suggesting microbiota negatively regulate Hnf4a. In support, analysis of genomic architecture in mouse intestinal epithelial cells disclosed that microbiota colonization leads to activation or inactivation of hundreds of enhancers along with drastic genome-wide reduction of HNF4A and HNF4G occupancy. Interspecies meta-analysis suggested interactions between HNF4A and microbiota promote gene expression patterns associated with human inflammatory bowel diseases. These results indicate a critical and conserved role for HNF4A in maintaining intestinal homeostasis in response to microbiota.
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Affiliation(s)
- James M Davison
- Department of Molecular Genetics and Microbiology, Center for the Genomics of Microbial Systems, Duke University, Durham, North Carolina 27710, USA.,Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA
| | - Colin R Lickwar
- Department of Molecular Genetics and Microbiology, Center for the Genomics of Microbial Systems, Duke University, Durham, North Carolina 27710, USA
| | - Lingyun Song
- Department of Pediatrics, Division of Medical Genetics, Center for Genomic and Computational Biology, Duke University, Durham, North Carolina 27708, USA
| | - Ghislain Breton
- Department of Integrative Biology and Pharmacology, McGovern Medical School, Houston, Texas 77030, USA
| | - Gregory E Crawford
- Department of Pediatrics, Division of Medical Genetics, Center for Genomic and Computational Biology, Duke University, Durham, North Carolina 27708, USA
| | - John F Rawls
- Department of Molecular Genetics and Microbiology, Center for the Genomics of Microbial Systems, Duke University, Durham, North Carolina 27710, USA
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Gabbani T, Deiana S, Marocchi M, Annese V. Genetic risk variants as therapeutic targets for Crohn's disease. Expert Opin Ther Targets 2017; 21:381-390. [PMID: 28281904 DOI: 10.1080/14728222.2017.1296431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 02/14/2017] [Indexed: 02/06/2023]
Abstract
The pathogenesis of Inflammatory bowel diseases (IBD) is multifactorial, with interactions between genetic and environmental factors. Despite the existence of genetic factors being largely demonstrated by epidemiological data and several genetic studies, only a few findings have been useful in term of disease prediction, disease progression and targeting therapy. Areas covered: This review summarizes the results of genome-wide association studies in Crohn's disease, the role of epigenetics and the recent discovery by genetic studies of new pathogenetic pathways. Furthermore, it focuses on the importance of applying genetic data to clinical practice, and more specifically how to better target therapy and predict potential drug-related toxicity. Expert opinion: Some genetic markers identified in Crohn`s disease have allowed investigators to hypothesize about, and in some cases, prove the usefulness of new specific therapeutic agents. However, the heterogeneity and complexity of this disease has so far limited the daily clinical use of genetic information. Finally, the study of the implications of genetics on therapy, either to predict efficacy or avoid toxicity, is considered still to be in its infancy.
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Affiliation(s)
- Tommaso Gabbani
- a Gastroenterology UO , Azienda Unita Sanitaria Locale della Romagna , Forlì , Italy
| | - Simona Deiana
- b Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Margherita Marocchi
- c Division of Gastroenterology , AOU Modena University Hospital , Modena , Italy
| | - Vito Annese
- d Department of Gastroenterology , Valiant Clinic , Dubai , UAE
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24
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Gabbani T, Deiana S, Annese AL, Lunardi S, Annese V. The genetic burden of inflammatory bowel diseases: implications for the clinic? Expert Rev Gastroenterol Hepatol 2016; 10:1109-1117. [PMID: 27258545 DOI: 10.1080/17474124.2016.1196131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel diseases (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic intestinal inflammation. Their etiology is multifactorial, with complex interactions between genetic and environmental factors, which are still largely unclear. Areas covered: The influence of genetics is clearly demonstrated by important epidemiological data, including familial aggregation and concordance in twins. In 2001, the first genetic susceptibility gene for IBD, the NOD2 gene, was identified. Currently, thanks to genetic wide association studies, over 200 susceptibility genetic markers are know. Expert commentary: However, clinically highly relevant gene associations are still very limited and the usefulness of these information in the current clinical strategies for treatment and surveillance of IBD is weak. Nevertheless, the recent identification of some genetic risk variants has clarified some newbiological pathways of these diseases thus paving the way for the discoveries in the near future of new targeted therapies.
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Affiliation(s)
- Tommaso Gabbani
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Simona Deiana
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Antonio Luca Annese
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Sarah Lunardi
- b Division of Internal Medicine 4 , AOU Careggi University Hospital , Florence , Italy
| | - Vito Annese
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
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Metzger J, Pfahler S, Distl O. Variant detection and runs of homozygosity in next generation sequencing data elucidate the genetic background of Lundehund syndrome. BMC Genomics 2016; 17:535. [PMID: 27485430 PMCID: PMC4971756 DOI: 10.1186/s12864-016-2844-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 06/17/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The Lundehund is a highly specialized breed characterized by a unique flexibility of the joints and polydactyly in all four limbs. The extremely small population size and high inbreeding has promoted a high frequency of diseased dogs affected by the Lundehund syndrome (LS), a severe gastro-enteropathic disease. RESULTS Comprehensive analysis of bead chip and whole-genome sequencing data for LS in the Lundehund resulted in a genome-wide association signal on CFA 34 and LS-specific runs of homozygosity (ROH) in this region. Filtering analysis for variants with predicted high or moderate effects revealed a missense mutation in LEPREL1 1.2 Mb proximal to the region of the genome-wide association, which was shown to be significantly associated with LS. LS-affected Lundehund harbored the mutant LEPREL1:g.139212C>G genotype A/A whereas all controls of other breeds showed the C/C wild type. In addition, ROH analysis for the Lundehund indicated a high enrichment of genes in potential signatures of selection affecting protein activation and immunoregulatory processes like NOD1 potentially involved in LS breed disposition. CONCLUSIONS Sequencing results for Lundehund specific traits reveal a potential causative mutation for LS in the neuropeptide operating gene LEPREL1 and suggests it as a precursor of the inflammatory process. Analyses of ROH regions give an insight into the genetic background of characteristic traits in the Lundehund that remain to be elucidated in the future.
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Affiliation(s)
- Julia Metzger
- Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover Foundation, Hanover, Germany.
| | - Sophia Pfahler
- Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover Foundation, Hanover, Germany
| | - Ottmar Distl
- Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover Foundation, Hanover, Germany
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26
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Epistatic interaction between TLR4 and NOD2 in patients with Crohn's Disease: relation with risk and phenotype in a Spanish cohort. Immunobiology 2016; 221:927-33. [PMID: 27290609 DOI: 10.1016/j.imbio.2016.05.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Revised: 05/18/2016] [Accepted: 05/27/2016] [Indexed: 01/11/2023]
Abstract
Crohn's Disease is one of the two major forms of the Inflammatory Bowel Diseases and, although the etiology is not completely understood, the confluence of environmental and genetic factors has been demonstrated. The aim of this study was to determine the distribution of TLR4 variants in a Spanish cohort of Crohn's Disease patients and their relation with phenotype and common NOD2 variants. A total of 371 Crohn's Disease (CD) patients and 636 healthy controls (HC) were included. Single Nucleotide Polimorphisms (SNPs) in TLR4 (D299G and T399I) and NOD2 (R702W and G908R) detection was performed by a Taqman(®) Allelic Discrimination Assay. 1007insC NOD2 variant was analyzed using a PCR combined with fluorescent technology and the different alleles were determined depending on the PCR products size. D299G and T399I were related to CD only in patients carrying NOD2 variants (NOD2+/TLR4+ haplotype) (p=0.036; OR=1.924), increasing the risk to develop CD when 1007insC and TLR4 variants were both present (OR=4.886). We also described a strong association between mutant NOD2 and CD risk (p<0.001, OR=3.214). R702W, G908R and 1007insC were associated when they were considered separately (p<0.001; p=0.002; p<0.001, respectively). Moreover, the patients carrying any mutant D299G or T399I polymorphisms were predisposed to develop a stricturing disease (p=0.013; OR=2.391), especially in the presence of NOD2 mutation (p=0.002; OR=4.989). In this study, ileal disease was also associated with the presence of at least one NOD2 susceptibility allele (p=0.001; OR=3.838) and, the risk of ileal CD was increased if TLR4 variants were presents (p<0.050; OR=4.160). TLR4 variants were related to bowel perforation, independently of NOD2.
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27
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Jiang D, Zhong S, McPeek MS. Retrospective Binary-Trait Association Test Elucidates Genetic Architecture of Crohn Disease. Am J Hum Genet 2016; 98:243-55. [PMID: 26833331 PMCID: PMC4746383 DOI: 10.1016/j.ajhg.2015.12.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 12/11/2015] [Indexed: 01/01/2023] Open
Abstract
In genetic association testing, failure to properly control for population structure can lead to severely inflated type 1 error and power loss. Meanwhile, adjustment for relevant covariates is often desirable and sometimes necessary to protect against spurious association and to improve power. Many recent methods to account for population structure and covariates are based on linear mixed models (LMMs), which are primarily designed for quantitative traits. For binary traits, however, LMM is a misspecified model and can lead to deteriorated performance. We propose CARAT, a binary-trait association testing approach based on a mixed-effects quasi-likelihood framework, which exploits the dichotomous nature of the trait and achieves computational efficiency through estimating equations. We show in simulation studies that CARAT consistently outperforms existing methods and maintains high power in a wide range of population structure settings and trait models. Furthermore, CARAT is based on a retrospective approach, which is robust to misspecification of the phenotype model. We apply our approach to a genome-wide analysis of Crohn disease, in which we replicate association with 17 previously identified regions. Moreover, our analysis on 5p13.1, an extensively reported region of association, shows evidence for the presence of multiple independent association signals in the region. This example shows how CARAT can leverage known disease risk factors to shed light on the genetic architecture of complex traits.
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Affiliation(s)
- Duo Jiang
- Department of Statistics, Oregon State University, Corvallis, OR 97331, USA
| | - Sheng Zhong
- Department of Statistics, University of Chicago, Chicago, IL 60637, USA
| | - Mary Sara McPeek
- Department of Statistics, University of Chicago, Chicago, IL 60637, USA; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
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Kumar M, Hemalatha R, Nagpal R, Singh B, Parasannanavar D, Verma V, Kumar A, Marotta F, Catanzaro R, Cuffari B, Jain S, Bissi L, Yadav H. PROBIOTIC APPROACHES FOR TARGETING INFLAMMATORY BOWEL DISEASE: AN UPDATE ON ADVANCES AND OPPORTUNITIES IN MANAGING THE DISEASE. INTERNATIONAL JOURNAL OF PROBIOTICS & PREBIOTICS 2016; 11:99-116. [PMID: 31452650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 09/28/2022]
Abstract
Various commensal enteric and pathogenic bacteria may be involved in the pathogenesis of inflammatory bowel diseases (IBDs), a chronic condition with a pathogenic background that involves both immunogenetic and environmental factors. IBDs comprising of Crohn's disease, and ulcerative colitis, and pauchitis are chronic inflammatory conditions, and known for causing disturbed homeostatic balance among the intestinal immune compartment, gut epithelium and microbiome. An increasing trend of IBDs in incidence, prevalence, and severity has been reported during recent years. Probiotic strains have been reported to manage the IBDs and related pathologies, and hence are current hot topics of research for their potential to manage metabolic diseases as well as various immunopathologies. However, the probiotics industry will need to undergo a transformation, with increased focus on stringent manufacturing guidelines and high-quality clinical trials. This article reviews the present state of art of role of probiotic bacteria in reducing inflammation and strengthening the host immune system with reference to the management of IBDs. We infer that t healthcare will move beyond its prevailing focus on human physiology, and embrace the superorganism as a paradigm to understand and ameliorate IBDs.
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Affiliation(s)
- Manoj Kumar
- Department of Microbiology and Immunology, National Institute of Nutrition, Hyderabad
| | - Rajkumar Hemalatha
- Department of Microbiology and Immunology, National Institute of Nutrition, Hyderabad
| | - Ravinder Nagpal
- Probiotics Research Laboratory, Graduate School of Medicine, Juntendo University, Tokyo
| | - Birbal Singh
- Indian Veterinary Research Institute, Regional Station, Palampur, India
| | - Devraj Parasannanavar
- Department of Microbiology and Immunology, National Institute of Nutrition, Hyderabad
| | - Vinod Verma
- Centre of Biotechnology, Nehru Science Complex, University of Allahabad, Allahabad, India
| | - Ashok Kumar
- Department of Zoology, M.L.K. Post-Graduate College, Balrampur (U.P.), India
| | - Francesco Marotta
- ReGenera Research Group for Aging Intervention & MMC-Milano Medical, Milano, Italy
| | - Roberto Catanzaro
- Department of Internal Medicine, University of Catania, Catania, Italy
| | - Biagio Cuffari
- Department of Internal Medicine, University of Catania, Catania, Italy
| | - Shalini Jain
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Laura Bissi
- ReGenera Research Group for Aging Intervention & MMC-Milano Medical, Milano, Italy
| | - Hariom Yadav
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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Pang S, Shen J, Liu Y, Chen F, Zheng Z, James AW, Hsu CY, Zhang H, Lee KS, Wang C, Li C, Chen X, Jia H, Zhang X, Soo C, Ting K. Proliferation and osteogenic differentiation of mesenchymal stem cells induced by a short isoform of NELL-1. Stem Cells 2015; 33:904-15. [PMID: 25376942 DOI: 10.1002/stem.1884] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 09/19/2014] [Accepted: 09/27/2014] [Indexed: 01/11/2023]
Abstract
Neural epidermal growth factor-like (NEL)-like protein 1 (NELL-1) has been identified as an osteoinductive differentiation factor that promotes mesenchymal stem cell (MSC) osteogenic differentiation. In addition to full-length NELL-1, there are several NELL-1-related transcripts reported. We used rapid amplification of cDNA ends to recover potential cDNA of NELL-1 isoforms. A NELL-1 isoform with the N-terminal 240 amino acid (aa) residues truncated was identified. While full-length NELL-1 that contains 810 aa residues (NELL-1810 ) plays an important role in embryologic skeletal development, the N-terminal-truncated NELL-1 isoform (NELL-1570 ) was expressed postnatally. Similar to NELL-1810 , NELL-1570 induced MSC osteogenic differentiation. In addition, NELL-1570 significantly stimulated MSC proliferation in multiple MSC-like populations such as murine C3H10T1/2 MSC cell line, mouse primary MSCs, and perivascular stem cells, which is a type of stem cells proposed as the perivascular origin of MSCs. In contrast, NELL-1810 demonstrated only limited stimulation of MSC proliferation. Similar to NELL-1810 , NELL-1570 was found to be secreted from host cells. Both NELL-1570 expression lentiviral vector and column-purified recombinant protein NELL-1570 demonstrated almost identical effects in MSC proliferation and osteogenic differentiation, suggesting that NELL-1570 may function as a pro-osteogenic growth factor. In vivo, NELL-1570 induced significant calvarial defect regeneration accompanied by increased cell proliferation. Thus, NELL-1570 has the potential to be used for cell-based or hormone-based therapy of bone regeneration.
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Affiliation(s)
- Shen Pang
- UCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California, Los Angeles, California, USA
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Mathieu F, Etain B, Dizier MH, Lajnef M, Lathrop M, Cabon C, Leboyer M, Henry C, Bellivier F. Genetics of emotional reactivity in bipolar disorders. J Affect Disord 2015; 188:101-6. [PMID: 26349599 DOI: 10.1016/j.jad.2015.08.037] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Revised: 08/12/2015] [Accepted: 08/17/2015] [Indexed: 10/23/2022]
Abstract
BACKGROUND Emotional reactivity has been proposed as a relevant intermediate phenotype of bipolar disorder (BD). Our goal was to identify genetic factors underlying emotional reactivity in a sample of bipolar patients. METHODS Affect intensity (a proxy measure of emotional reactivity) was measured in a sample of 281 euthymic patients meeting DSM-IV criteria for BD. We use a validated dimensional tool, the 40-item self-report Affect Intensity Measure scale developed by Larsen and Diener. Patients with BD were genotyped for 475. 740 SNPs (using Illumina HumanHap550 Beadchips or HumanHap610 Quad chip). Association was investigated with a general mixed regression model of the continuous trait against genotypes, including gender as covariate. RESULTS Four regions (1p31.3, 3q13.11, 11p15.1 and 11q14.4) with a p-value lower or equal to 5×10(-6) were identified. In these regions, the joint effect of the four variants accounted for 24.5% of the variance of AIM score. Epistasis analysis did not detect interaction between these variants. In the 11p15.1 region, the rs10766743 located in the intron of the NELL1 gene remained significant after correction for multiple testing (p=2×10(-7)). CONCLUSIONS These findings illustrate that focusing on quantitative intermediate phenotypes can facilitate the identification of genetic susceptibility variants in BD.
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Affiliation(s)
- F Mathieu
- Inserm, UMRS-958, Paris, France; Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
| | - B Etain
- INSERM U955, Equipe de Psychiatrie Translationelle, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France; AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France; Fondation FondaMental, Créteil, France
| | - M H Dizier
- Université Paris-Diderot, Sorbonne Paris Cité, Paris, France; INSERM, UMR-S946, Paris, France
| | - M Lajnef
- INSERM U955, Equipe de Psychiatrie Translationelle, Créteil, France
| | - M Lathrop
- Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France
| | - C Cabon
- AP-HP, Groupe Hospitalier Henri Mondor, Plateforme de Ressources Biologiques Centre d'Investigation Clinique, Créteil F-94000, France; AP-HP, Groupe Hospitalier Saint-Louis, Lariboisière, F. Widal, Service de Psychiatrie, Paris; INSERM U955, Equipe de Psychiatrie Translationelle, Créteil, France
| | - M Leboyer
- INSERM U955, Equipe de Psychiatrie Translationelle, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France; AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France; Fondation FondaMental, Créteil, France
| | - C Henry
- INSERM U955, Equipe de Psychiatrie Translationelle, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France; AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France; Fondation FondaMental, Créteil, France
| | - F Bellivier
- Université Paris-Diderot, Sorbonne Paris Cité, Paris, France; Fondation FondaMental, Créteil, France; INSERM UMR-S1144, Paris, France
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Daya M, van der Merwe L, van Helden PD, Möller M, Hoal EG. Investigating the Role of Gene-Gene Interactions in TB Susceptibility. PLoS One 2015; 10:e0123970. [PMID: 25919455 PMCID: PMC4412713 DOI: 10.1371/journal.pone.0123970] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 02/24/2015] [Indexed: 11/22/2022] Open
Abstract
Tuberculosis (TB) is the second leading cause of mortality from infectious disease worldwide. One of the factors involved in developing disease is the genetics of the host, yet the field of TB susceptibility genetics has not yielded the answers that were expected. A commonly posited explanation for the missing heritability of complex disease is gene-gene interactions, also referred to as epistasis. In this study we investigate the role of gene-gene interactions in genetic susceptibility to TB using a cohort recruited from a high TB incidence community from Cape Town, South Africa. Our discovery data set incorporates genotypes from a large a number of candidate gene studies as well as genome-wide data. After limiting our search space to pairs of putative TB susceptibility genes, as well as pairs of genes that have been curated in online databases as potential interactors, we use statistical modelling to identify pairs of interacting SNPs. We attempt to validate the top models identified in our discovery data set using an independent genome-wide TB case-control data set from The Gambia. A number of models were successfully validated, indicating that interplay between the NRG1 - NRG3, GRIK1 - GRIK3 and IL23R - ATG4C gene pairs may modify susceptibility to TB. Gene pairs involved in the NF-κB pathway were also identified in the discovery data set (SFTPD - NOD2, ISG15 - TLR8 and NLRC5 - IL12RB1), but could not be tested in the Gambian study group due to lack of overlapping data.
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Affiliation(s)
- Michelle Daya
- SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Lize van der Merwe
- SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Paul D. van Helden
- SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Marlo Möller
- SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Eileen G. Hoal
- SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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Hulur I, Gamazon ER, Skol AD, Xicola RM, Llor X, Onel K, Ellis NA, Kupfer SS. Enrichment of inflammatory bowel disease and colorectal cancer risk variants in colon expression quantitative trait loci. BMC Genomics 2015; 16:138. [PMID: 25766683 PMCID: PMC4351699 DOI: 10.1186/s12864-015-1292-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 01/29/2015] [Indexed: 12/20/2022] Open
Abstract
Background Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with diseases of the colon including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). However, the functional role of many of these SNPs is largely unknown and tissue-specific resources are lacking. Expression quantitative trait loci (eQTL) mapping identifies target genes of disease-associated SNPs. This study provides a comprehensive eQTL map of distal colonic samples obtained from 40 healthy African Americans and demonstrates their relevance for GWAS of colonic diseases. Results 8.4 million imputed SNPs were tested for their associations with 16,252 expression probes representing 12,363 unique genes. 1,941 significant cis-eQTL, corresponding to 122 independent signals, were identified at a false discovery rate (FDR) of 0.01. Overall, among colon cis-eQTL, there was significant enrichment for GWAS variants for IBD (Crohn’s disease [CD] and ulcerative colitis [UC]) and CRC as well as type 2 diabetes and body mass index. ERAP2, ADCY3, INPP5E, UBA7, SFMBT1, NXPE1 and REXO2 were identified as target genes for IBD-associated variants. The CRC-associated eQTL rs3802842 was associated with the expression of C11orf93 (COLCA2). Enrichment of colon eQTL near transcription start sites and for active histone marks was demonstrated, and eQTL with high population differentiation were identified. Conclusions Through the comprehensive study of eQTL in the human colon, this study identified novel target genes for IBD- and CRC-associated genetic variants. Moreover, bioinformatic characterization of colon eQTL provides a tissue-specific tool to improve understanding of biological differences in diseases between different ethnic groups. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1292-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Imge Hulur
- Committee on Genetics, Genomics and Systems Biology, Chicago, IL, 60637, USA.
| | - Eric R Gamazon
- Department of Medicine, 900 East 57th Street, MB#9, Chicago, IL, 60637, USA. .,Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, 37232, USA.
| | - Andrew D Skol
- Department of Medicine, 900 East 57th Street, MB#9, Chicago, IL, 60637, USA.
| | - Rosa M Xicola
- Department of Medicine, Yale University, New Haven, CT, 06510, USA.
| | - Xavier Llor
- Department of Medicine, Yale University, New Haven, CT, 06510, USA.
| | - Kenan Onel
- Department of Pediatrics, University of Chicago, Chicago, IL, 60637, USA.
| | - Nathan A Ellis
- University of Arizona Cancer Center, Tucson, AZ, 85724, USA.
| | - Sonia S Kupfer
- Department of Medicine, 900 East 57th Street, MB#9, Chicago, IL, 60637, USA.
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Ellinghaus D, Bethune J, Petersen BS, Franke A. The genetics of Crohn's disease and ulcerative colitis--status quo and beyond. Scand J Gastroenterol 2015; 50:13-23. [PMID: 25523552 DOI: 10.3109/00365521.2014.990507] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The two major subtypes of inflammatory bowel disease (IBD), ulcerative colitis (UC, MIM#191390) and Crohn's disease (CD, MIM#266600), are chronic relapsing-remitting inflammatory disorders affecting primarily the gastrointestinal tract. Prevalence rates in North America and Europe range from 21 to 246 per 100,000 for UC and 8 to 214 per 100,000 for CD. Although CD and UC share some clinical and pathological features, they can be distinguished by localization, endoscopic appearance, histology and behavior, which suggest differences in the underlying pathophysiology. The importance of genetic risk factors in disease etiology is high and has been documented more clearly for CD than for UC (relative sibling risks λ(s): 15-35 for CD, 6-9 for UC). The most recent and largest genetic association study for IBD, which employed genome-wide association data for over 75,000 patients and controls, established the association of 163 susceptibility loci with IBD. Although the disease variance explained by the 163 loci only amounts to 13.6% for CD and 7.5% for UC, the identified loci and the candidate genes within yielded valuable insights into the pathogenesis of IBD and the relevant disease pathways. We here review the current research on the genetics of IBD and provide insights into on current efforts as well as suggest topics for future research.
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Affiliation(s)
- David Ellinghaus
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel , Kiel , Germany
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Abstract
Technological advances in the large scale analysis of human genetics have generated profound insights into possible genetic contributions to chronic diseases including the inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis. To date, 163 distinct genetic risk loci have been associated with either Crohn's disease or ulcerative colitis, with a substantial degree of genetic overlap between these 2 conditions. Although many risk variants show a reproducible correlation with disease, individual gene associations only affect a subset of patients, and the functional contribution(s) of these risk variants to the onset of IBD is largely undetermined. Although studies in twins have demonstrated that the development of IBD is not mediated solely by genetic risk, it is nevertheless important to elucidate the functional consequences of risk variants for gene function in relevant cell types known to regulate key physiological processes that are compromised in IBD. This article will discuss IBD candidate genes that are known to be, or are suspected of being, involved in regulating the intestinal epithelial barrier and several of the physiological processes presided over by this dynamic and versatile layer of cells. This will include assembly and regulation of tight junctions, cell adhesion and polarity, mucus and glycoprotein regulation, bacterial sensing, membrane transport, epithelial differentiation, and restitution.
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Abstract
PURPOSE Variants modulating expression of the prostaglandin receptor 4 (PTGER4) have been reported to be associated with Cohn's disease (CD), but the clinical impact remains to be elucidated. We analyzed these variants in a large German inflammatory bowel disease (IBD) cohort and searched for a potential phenotype association. METHODS The variants rs4495224 and rs7720838 were studied in adult German IBD patients (CD, n = 475; ulcerative colitis (UC), n = 293) and healthy controls (HC, n = 467). Data were correlated to results from NOD2 genotyping and to clinical characteristics. RESULTS We found a significant association for the rs7720838 variant with overrepresentation of the T allele to CD (p = 0.0058; OR 0.7703, 95 % CI 0.641-0.926) but not to UC. Furthermore, logistic regression analysis revealed that the presence of the T allele was associated with stricturing disease behavior in CD patients (p = 0.03; OR 1.84, 95 % CI 1.07-3.16). Interestingly, the chance for developing stricturing disease behavior was enhanced if mutant alleles in both rs7720838 and NOD2 were present (OR 2.87, 95 % CI 1.42-5.81; p = 0.003). No overall association to CD or UC was found for the rs4495224 variant. CONCLUSIONS The PTGER4 modulating variant rs7720838 increases susceptibility for CD and might resemble a risk factor for stricturing disease behavior.
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Jakobsen C, Cleynen I, Andersen PS, Vermeire S, Munkholm P, Paerregaard A, Wewer V. Genetic susceptibility and genotype-phenotype association in 588 Danish children with inflammatory bowel disease. J Crohns Colitis 2014; 8:678-85. [PMID: 24394805 DOI: 10.1016/j.crohns.2013.12.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 11/28/2013] [Accepted: 12/15/2013] [Indexed: 02/06/2023]
Abstract
AIM To investigate the association between known inflammatory bowel disease (IBD)-associated genetic variants and development of paediatric IBD, and specific clinical sub-phenotypes. MATERIAL AND METHODS In this case-control study we included IBD patients <18 years of age at diagnosis from the Danish National Patient Registry and healthy children <18 years of age were randomly selected from the Danish Central Office of Civil Registration. The latter had filled out a questionnaire regarding health status, and DNA was obtained from blood samples and the buccal mucosa. Patient files were retrieved and clinical information was extracted. DNA was obtained from Guthrie cards from the Danish National Neonatal Screening Biobank (PKU-biobanken) at Statens Serum Institut and from blood samples. RESULTS A total of 588 IBD patients (244 Crohn's disease (CD), 318 ulcerative colitis (UC) and 26 IBD-unclassified (IBDU)) and 543 healthy controls were included. We found an association between CD and rs22411880 (ATG16L1, odds ratio (OR)=1.7 [1.1-1.7], p=0.003), rs5743289 (NOD2, OR=1.4 [1.1-1.9], p=0.009) and the paediatric specific rs1250550 (ZMIZ1, OR=0.7 [0.5-0.9], p=0.01). None of the investigated 41 SNPs were associated with disease localisation, medical treatment or surgery after correcting for multiple analyses. CONCLUSION We found an association between CD and three previously published genetic variants and replicated the association with the paediatric specific ZMIZ1 gene. No Bonferroni corrected significant genotype-phenotype associations were found. For future studies aimed at finding predictors for disease course in (paediatric) IBD, it will be worthwhile to include a combination of genetic, clinical and serological markers.
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Affiliation(s)
- C Jakobsen
- Department of Paediatrics, Hvidovre University Hospital, Copenhagen, Denmark.
| | - I Cleynen
- Department of Clinical and Experimental Medicine, KU Leuven, Belgium
| | - P S Andersen
- Department of Microbiology and Infection Control, State Serum Institute, Copenhagen, Denmark
| | - S Vermeire
- Department of Gastroenterology, University Hospitals Leuven, Belgium
| | - P Munkholm
- Department of Gastroenterology, Medical Section, Herlev University Hospital, Copenhagen, Denmark
| | - A Paerregaard
- Department of Paediatrics, Hvidovre University Hospital, Copenhagen, Denmark
| | - V Wewer
- Department of Paediatrics, Hvidovre University Hospital, Copenhagen, Denmark
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Liu JZ, Anderson CA. Genetic studies of Crohn's disease: past, present and future. Best Pract Res Clin Gastroenterol 2014; 28:373-86. [PMID: 24913378 PMCID: PMC4075408 DOI: 10.1016/j.bpg.2014.04.009] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 04/14/2014] [Accepted: 04/24/2014] [Indexed: 01/31/2023]
Abstract
The exact aetiology of Crohn's disease is unknown, though it is clear from early epidemiological studies that a combination of genetic and environmental risk factors contributes to an individual's disease susceptibility. Here, we review the history of gene-mapping studies of Crohn's disease, from the linkage-based studies that first implicated the NOD2 locus, through to modern-day genome-wide association studies that have discovered over 140 loci associated with Crohn's disease and yielded novel insights into the biological pathways underlying pathogenesis. We describe on-going and future gene-mapping studies that utilise next generation sequencing technology to pinpoint causal variants and identify rare genetic variation underlying Crohn's disease risk. We comment on the utility of genetic markers for predicting an individual's disease risk and discuss their potential for identifying novel drug targets and influencing disease management. Finally, we describe how these studies have shaped and continue to shape our understanding of the genetic architecture of Crohn's disease.
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Affiliation(s)
- Jimmy Z Liu
- The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
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Negi S, Juyal G, Senapati S, Prasad P, Gupta A, Singh S, Kashyap S, Kumar A, Kumar U, Gupta R, Kaur S, Agrawal S, Aggarwal A, Ott J, Jain S, Juyal RC, Thelma BK. A genome-wide association study reveals ARL15, a novel non-HLA susceptibility gene for rheumatoid arthritis in North Indians. ACTA ACUST UNITED AC 2014; 65:3026-35. [PMID: 23918589 DOI: 10.1002/art.38110] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Accepted: 07/25/2013] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Genome-wide association studies (GWAS) and their subsequent meta-analyses have changed the landscape of genetics in rheumatoid arthritis (RA) by uncovering several novel genes. Such studies are heavily weighted by samples from Caucasian populations, but they explain only a small proportion of total heritability. Our previous studies in genetically distinct North Indian RA cohorts have demonstrated apparent allelic/genetic heterogeneity between North Indian and Western populations, warranting GWAS in non-European populations. We undertook this study to detect additional disease-associated loci that may be collectively important in the presence or absence of genes with a major effect. METHODS High-quality genotypes for >600,000 single-nucleotide polymorphisms (SNPs) in 706 RA patients and 761 controls from North India were generated in the discovery stage. Twelve SNPs showing suggestive association (P < 5 × 10(-5)) were then tested in an independent cohort of 927 RA patients and 1,148 controls. Additional disease-associated loci were determined using support vector machine (SVM) analyses. Fine-mapping of novel loci was performed by using imputation. RESULTS In addition to the expected association of the HLA locus with RA, we identified association with a novel intronic SNP of ARL15 (rs255758) on chromosome 5 (Pcombined = 6.57 × 10(-6); odds ratio 1.42). Genotype-phenotype correlation by assaying adiponectin levels demonstrated the functional significance of this novel gene in disease pathogenesis. SVM analysis confirmed this association along with that of a few more replication stage genes. CONCLUSION In this first GWAS of RA among North Indians, ARL15 emerged as a novel genetic risk factor in addition to the classic HLA locus, which suggests that population-specific genetic loci as well as those shared between Asian and European populations contribute to RA etiology. Furthermore, our study reveals the potential of machine learning methods in unraveling gene-gene interactions using GWAS data.
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Affiliation(s)
- Sapna Negi
- National Institute of Immunology, New Delhi, India
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Villani AC, Franchimont D. The contribution of genetic studies in shifting the immunopathogenesis paradigm of Crohn’s disease. Expert Rev Clin Immunol 2014; 5:361-4. [DOI: 10.1586/eci.09.21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Muise A, Rotin D. Apical junction complex proteins and ulcerative colitis: a focus on thePTPRSgene. Expert Rev Mol Diagn 2014; 8:465-77. [DOI: 10.1586/14737159.8.4.465] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Turner NJ, Londono R, Dearth CL, Culiat CT, Badylak SF. Human NELL1 protein augments constructive tissue remodeling with biologic scaffolds. Cells Tissues Organs 2013; 198:249-65. [PMID: 24335144 DOI: 10.1159/000356491] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/18/2013] [Indexed: 11/19/2022] Open
Abstract
Biologic scaffolds composed of extracellular matrix (ECM) derived from decellularized tissues effectively reprogram key stages of the mammalian response to injury, altering the wound microenvironment from one that promotes scar tissue formation to one that stimulates constructive and functional tissue remodeling. In contrast, engineered scaffolds, composed of purified ECM components such as collagen, lack the complex ultrastructure and composition of intact ECM and may promote wound healing but lack factors that facilitate constructive and functional tissue remodeling. The objective of the present study was to test the hypothesis that addition of NELL1, a signaling protein that controls cell growth and differentiation, enhances the constructive tissue remodeling of a purified collagen scaffold. An abdominal wall defect model in the rat of 1.5-cm(2) partial thickness was used to compare the constructive remodeling of a bovine type I collagen scaffold to a biologic scaffold derived from small intestinal submucosa (SIS)-ECM with and without augmentation with 17 μg NELL1 protein. Samples were evaluated histologically at 14 days and 4 months. The contractile response of the defect site was also evaluated at 4 months. Addition of NELL1 protein improved the constructive remodeling of collagen scaffolds but not SIS-ECM scaffolds. Results showed an increase in the contractile force of the remodeled skeletal muscle and a fast:slow muscle composition similar to native tissue in the collagen-treated group. The already robust remodeling response to SIS-ECM was not enhanced by NELL1 at the dose tested. These findings suggest that NELL1 protein does contribute to the enhanced constructive remodeling of skeletal muscle.
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Affiliation(s)
- Neill J Turner
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pa., USA
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Skieceviciene J, Kiudelis G, Ellinghaus E, Balschun T, Jonaitis LV, Zvirbliene A, Denapiene G, Leja M, Pranculiene G, Kalibatas V, Saadati H, Ellinghaus D, Andersen V, Valantinas J, Irnius A, Derovs A, Tamelis A, Schreiber S, Kupcinskas L, Franke A. Replication study of ulcerative colitis risk loci in a Lithuanian-Latvian case-control sample. Inflamm Bowel Dis 2013; 19:2349-2355. [PMID: 23974994 DOI: 10.1097/mib.0b013e3182a3eaeb] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Differences between populations might be reflected in their different genetic risk maps to complex diseases, for example, inflammatory bowel disease. We here investigated the role of known inflammatory bowel disease-associated single nucleotide polymorphisms (SNPs) in a subset of patients with ulcerative colitis (UC) from the Northeastern European countries Lithuania and Latvia and evaluated possible epistatic interactions between these genetic variants. METHODS We investigated 77 SNPs derived from 5 previously published genome-wide association studies for Crohn's disease and UC. Our study panel comprised 444 Lithuanian and Latvian patients with UC and 1154 healthy controls. Single marker case-control association and SNP-SNP epistasis analyses were performed. RESULTS We found 14 SNPs tagging 9 loci, including 21q21.1, NKX2-3, MST1, the HLA region, 1p36.13, IL10, JAK2, ORMDL3, and IL23R, to be associated with UC. Interestingly, the association of UC with previously identified variants in the HLA region was not the strongest association in our study (P = 4.34 × 10, odds ratio [OR] = 1.25), which is in contrast to all previously published studies. No association with any disease subphenotype was found. SNP-SNP interaction analysis showed significant epistasis between SNPs in the PTPN22 (rs2476601) and C13orf31 (rs3764147) genes and increased risk for UC (P = 1.64 × 10, OR = 2.44). The association has been confirmed in the Danish study group (P = 0.04, OR = 3.25). CONCLUSIONS We confirmed the association of the 9 loci (21q21.1, 1p36.13, NKX2-3, MST1, the HLA region, IL10, JAK2, ORMDL3, and IL23R) with UC in the Lithuanian-Latvian population. SNP-SNP interaction analyses showed that the combination of SNPs in the PTPN22 (rs2476601) and C13orf31 (rs3764147) genes increase the risk for UC.
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Affiliation(s)
- Jurgita Skieceviciene
- *Institute for Digestive Research and †Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania; ‡Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; §Center of Hepatology, Gastroenterology and Dietetics, Vilnius University, Vilnius, Lithuania; ¶Digestive Diseases Centre GASTRO, Riga, Latvia; Departments of ‖Children Diseases and **Health Management, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania; ††Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark; ‡‡Medical Department, Hospital of Southern Jutland, Aabenraa, Denmark; §§Internal Disease Department, Riga Stradins University, Riga, Latvia; and ¶¶Department of Surgery, Academy of Medicine, Lithuanian University of Health Science, Kaunas, Lithuania
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Glas J, Seiderer J, Czamara D, Pasciuto G, Diegelmann J, Wetzke M, Olszak T, Wolf C, Müller-Myhsok B, Balschun T, Achkar JP, Kamboh MI, Franke A, Duerr RH, Brand S. PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn's disease and affect NF-κB and XBP1 binding sites. PLoS One 2012; 7:e52873. [PMID: 23300802 PMCID: PMC3531335 DOI: 10.1371/journal.pone.0052873] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2012] [Accepted: 11/22/2012] [Indexed: 01/08/2023] Open
Abstract
Background Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes. Methodology/Principal Findings A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10−5; 0.76 [0.67–0.87]) and of rs7720838 (p = 6.91×10−4; 0.81 [0.71–0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10−7 for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD. Conclusions/Significance We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility.
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MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Binding Sites
- Child
- Chromosomes, Human, Pair 5/genetics
- Crohn Disease/genetics
- DNA-Binding Proteins/metabolism
- Epistasis, Genetic
- Female
- Gene Expression
- Gene Frequency
- Genetic Predisposition to Disease
- Humans
- Male
- Middle Aged
- NF-kappa B/metabolism
- Polymorphism, Single Nucleotide
- Receptors, Prostaglandin E, EP4 Subtype/genetics
- Receptors, Prostaglandin E, EP4 Subtype/metabolism
- Regulatory Factor X Transcription Factors
- Sequence Analysis, DNA
- Transcription Factors/metabolism
- X-Box Binding Protein 1
- Young Adult
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Affiliation(s)
- Jürgen Glas
- Department of Medicine II - Grosshadern, University of Munich, Munich, Germany
- Department of Preventive Dentistry and Periodontology, University of Munich, Munich, Germany
- Department of Human Genetics, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany
| | - Julia Seiderer
- Department of Medicine II - Grosshadern, University of Munich, Munich, Germany
| | | | - Giulia Pasciuto
- Department of Medicine II - Grosshadern, University of Munich, Munich, Germany
| | - Julia Diegelmann
- Department of Medicine II - Grosshadern, University of Munich, Munich, Germany
- Department of Preventive Dentistry and Periodontology, University of Munich, Munich, Germany
| | - Martin Wetzke
- Center for Pediatrics, Hannover Medical School, Hannover, Germany
| | - Torsten Olszak
- Department of Medicine II - Grosshadern, University of Munich, Munich, Germany
- Division of Gastroenterology, Brigham & Women's Hospital, Harvard Medical School, Boston, United States of America
| | | | | | - Tobias Balschun
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Jean-Paul Achkar
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
- Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - M. Ilyas Kamboh
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Richard H. Duerr
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Stephan Brand
- Department of Medicine II - Grosshadern, University of Munich, Munich, Germany
- * E-mail:
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Jung C, Colombel JF, Lemann M, Beaugerie L, Allez M, Cosnes J, Vernier-Massouille G, Gornet JM, Gendre JP, Cezard JP, Ruemmele FM, Turck D, Merlin F, Zouali H, Libersa C, Dieudé P, Soufir N, Thomas G, Hugot JP. Genotype/phenotype analyses for 53 Crohn's disease associated genetic polymorphisms. PLoS One 2012; 7:e52223. [PMID: 23300620 PMCID: PMC3531408 DOI: 10.1371/journal.pone.0052223] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2012] [Accepted: 11/16/2012] [Indexed: 12/18/2022] Open
Abstract
Background & Aims Recent studies reported a role for more than 70 genes or loci in the susceptibility to Crohn’s disease (CD). However, the impact of these associations in clinical practice remains to be defined. The aim of the study was to analyse the relationship between genotypes and phenotypes for the main 53 CD-associated polymorphisms. Method A cohort of 798 CD patients with a median follow up of 7 years was recruited by tertiary adult and paediatric gastroenterological centres. A detailed phenotypic description of the disease was recorded, including clinical presentation, response to treatments and complications. The participants were genotyped for 53 CD-associated variants previously reported in the literature and correlations with clinical sub-phenotypes were searched for. A replication cohort consisting of 722 CD patients was used to further explore the putative associations. Results The NOD2 rare variants were associated with an earlier age at diagnosis (p = 0.0001) and an ileal involvement (OR = 2.25[1.49–3.41] and 2.77 [1.71–4.50] for rs2066844 and rs2066847, respectively). Colonic lesions were positively associated with the risk alleles of IL23R rs11209026 (OR = 2.25 [1.13–4.51]) and 6q21 rs7746082 (OR = 1.60 [1.10–2.34] and negatively associated with the risk alleles of IRGM rs13361189 (OR = 0.29 [0.11–0.74]) and DEFB1 rs11362 (OR = 0.50 [0.30–0.80]). The ATG16L1 and IRGM variants were associated with a non-inflammatory behaviour (OR = 1.75 [1.22–2.53] and OR = 1.50 [1.04–2.16] respectively). However, these associations lost significance after multiple testing corrections. The protective effect of the IRGM risk allele on colonic lesions was the only association replicated in the second cohort (p = 0.03). Conclusions It is not recommended to genotype the studied polymorphisms in routine practice.
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Affiliation(s)
- Camille Jung
- Université Paris Diderot, UMR843, Paris, France
- UMR843, INSERM, Paris, France
- Service de Gastroentérologie Pédiatrique, Hôpital Robert Debré, APHP, Paris, France
| | | | - Marc Lemann
- Service de Gastroentérologie, Hôpital Saint-Louis, AP-HP, Université Paris- Diderot, Paris, France
| | - Laurent Beaugerie
- Department of Gastroenterology, Hôpital Saint-Antoine, AP-HP, and UPMC Univ Paris 06, Paris, France
| | - Matthieu Allez
- Service de Gastroentérologie, Hôpital Saint-Louis, AP-HP, Université Paris- Diderot, Paris, France
| | - Jacques Cosnes
- Department of Gastroenterology, Hôpital Saint-Antoine, AP-HP, and UPMC Univ Paris 06, Paris, France
| | | | - Jean-Marc Gornet
- Service de Gastroentérologie, Hôpital Saint-Louis, AP-HP, Université Paris- Diderot, Paris, France
| | - Jean-Pierre Gendre
- Department of Gastroenterology, Hôpital Saint-Antoine, AP-HP, and UPMC Univ Paris 06, Paris, France
| | - Jean-Pierre Cezard
- Service de Gastroentérologie Pédiatrique, Hôpital Robert Debré, APHP, Paris, France
| | - Frank M. Ruemmele
- Université Paris Descartes and Service de Gastroentérologie Pédiatrique, Hôpital Necker Enfants-Malades, APHP, Paris, France
| | - Dominique Turck
- Service de Gastroentérologie Pédiatrique, Hôpital Jeanne de Flandre, Université de Lille 2, Lille, France
| | - Françoise Merlin
- Université Paris Diderot, UMR843, Paris, France
- UMR843, INSERM, Paris, France
| | | | - Christian Libersa
- Centre D’Investigation Clinique 9301, Hôpital Cardiologique, INSERM, Lille, France
| | - Philippe Dieudé
- Université Paris Diderot and Service de Rhumatologie, Hôpital Bichat, Paris, France
| | - Nadem Soufir
- Université Paris Diderot and Service de Biochimie Génétique, Hôpital Bichat, Paris, France
| | | | - Jean-Pierre Hugot
- Université Paris Diderot, UMR843, Paris, France
- UMR843, INSERM, Paris, France
- Service de Gastroentérologie Pédiatrique, Hôpital Robert Debré, APHP, Paris, France
- * E-mail:
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45
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Connolly JJ, Glessner JT, Hakonarson H. A genome-wide association study of autism incorporating autism diagnostic interview-revised, autism diagnostic observation schedule, and social responsiveness scale. Child Dev 2012; 84:17-33. [PMID: 22935194 DOI: 10.1111/j.1467-8624.2012.01838.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Efforts to understand the causes of autism spectrum disorders (ASDs) have been hampered by genetic complexity and heterogeneity among individuals. One strategy for reducing complexity is to target endophenotypes, simpler biologically based measures that may involve fewer genes and constitute a more homogenous sample. A genome-wide association study of 2,165 participants (mean age = 8.95 years) examined associations between genomic loci and individual assessment items from the Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, and Social Responsiveness Scale. Significant associations with a number of loci were identified, including KCND2 (overly serious facial expressions), NOS2A (loss of motor skills), and NELL1 (faints, fits, or blackouts). These findings may help prioritize directions for future genomic efforts.
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46
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Lai LA, Risques RA, Bronner MP, Rabinovitch PS, Crispin D, Chen R, Brentnall TA. Pan-colonic field defects are detected by CGH in the colons of UC patients with dysplasia/cancer. Cancer Lett 2012; 320:180-8. [PMID: 22387989 PMCID: PMC3406733 DOI: 10.1016/j.canlet.2012.02.031] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Revised: 02/21/2012] [Accepted: 02/23/2012] [Indexed: 02/08/2023]
Abstract
BAC arrays were used to evaluate genomic instability along the colon of patients with ulcerative colitis (UC). Genomic instability increases with disease progression and biopsies more proximal to dysplasia showed increased instability. Pan-colonic field copy number gain or loss involving small (<1Mb) regions were detected in most patients and were particularly apparent in the UC progressor patients who had dysplasia or cancer. Chromosomal copy gains or losses affecting large regions were mainly restricted to dysplastic biopsies. Areas of significant chromosomal losses were detected in the UC progressors on chromosomes 2q36, 3q25, 3p21, 4q34, 4p16.2, 15q22, and 16p13 (p-value⩽0.04). These results extend our understanding of the dynamic nature of pan-colonic genomic instability in this disease.
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Affiliation(s)
- Lisa A Lai
- Department of Medicine, University of Washington, Seattle, WA, United States
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47
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Bartolomé N, Szczypiorska M, Sánchez A, Sanz J, Juanola-Roura X, Gratacós J, Zarco-Montejo P, Collantes E, Martínez A, Tejedor D, Artieda M, Mulero J. Genetic polymorphisms inside and outside the MHC improve prediction of AS radiographic severity in addition to clinical variables. Rheumatology (Oxford) 2012; 51:1471-8. [PMID: 22495925 DOI: 10.1093/rheumatology/kes056] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE The aim of this study was to analyse if single nucleotide polymorphisms (SNPs) inside and outside the MHC region might improve the prediction of radiographic severity in AS. METHODS A cross-sectional multi-centre study was performed including 473 Spanish AS patients previously diagnosed with AS following the Modified New York Criteria and with at least 10 years of follow-up from the first symptoms of AS. Clinical variables and 384 SNPs were analysed to predict radiographic severity [BASRI-total (BASRI-t) corrected for the duration of AS since first symptoms] using multivariate forward logistic regression. Predictive power was measured by the area under the receiver operating characteristic curve (AUC), specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS The model with the best fit measured radiographic severity as the BASRI-t 60th percentile and combined eight variables: male gender, older age at disease onset and six SNPs at ADRB1 (rs1801253), NELL1 (rs8176785) and MHC (rs1634747, rs9270986, rs7451962 and rs241453) genes. The model predictive power was defined by AUC = 0.76 (95% CI 0.71, 0.80), being significantly better than the model with only clinical variables, AUC = 0.68 (95% CI 0.63, 0.73), P = 0.0004. Internal split-sample analysis proved the validation of the model. Patient genotype for SNPs outside the MHC region, inside the MHC region and clinical variables account for 26, 38 and 36%, respectively, of the explained variability on radiographic severity prediction. CONCLUSION Prediction of radiographic severity in AS based on clinical variables can be significantly improved by including SNPs both inside and outside the MHC region.
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Affiliation(s)
- Nerea Bartolomé
- Diagnostic Department, Progenika Biopharma SA, Parque Tecnológico de Bizkaia, Edificio 504, Derio 48160, Bizkaia, Spain.
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48
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Murdoch TB, Bernstein CN, El-Gabalawy H, Stempak JM, Sargent M, Elias B, Xu W, Pathan S, Silverberg MS. Prevalence of genetic variants associated with inflammatory bowel disease in a healthy First Nations cohort. CMAJ 2012; 184:E435-41. [PMID: 22496383 DOI: 10.1503/cmaj.110613] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Inflammatory bowel disease is the result of both genes and environment. Canadian First Nations people, despite living in a region with a high prevalence of inflammatory bowel disease, are relatively protected from this disease. We aimed to compare the carriage of genetic variants associated with inflammatory bowel disease in healthy First Nations and white people. METHODS DNA was extracted from the venous blood of healthy First Nations (n = 340) and white (n = 285) participants from Manitoba. Genotyping was performed for 69 single nucleotide polymorphisms (SNPs) with known or suspected associations with inflammatory bowel disease. We compared the genotypes between groups by logistic regression, adjusting for multiple testing. We calculated a risk score for the NOD2 gene by adding the number of risk alleles at three important NOD2 SNPs (G908R, R702W and 3020insC). RESULTS We found genetic variation between white and First Nations participants at 45 of 69 SNPs. Notably, carriage of the ATG16L1 T300A mutation was lower in First Nations participants (p = 4.1 × 10(-30)). Cumulative carriage of important NOD2 variants was significantly lower among First Nations participants (3.9% v. 15.2%; p < 0.0001 for risk score) than among white participants. Risk variants in IL23R (p = 0.014) and IL12B (p = 1.2 × 10(-16)), among others, were more prevalent among First Nations participants than among white participants. INTERPRETATION The low prevalence of variants associated with bacterial processing and handling in First Nations people may explain their relative protection from inflammatory bowel disease. Increased carriage of a number of risk variants, for example in the interleukin-23/Th17 pathway, is especially intriguing given their importance in other inflammatory diseases of high incidence in First Nations populations.
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Affiliation(s)
- Travis B Murdoch
- Inflammatory Bowel Disease Group, Mount Sinai Hospital, University of Toronto, Toronto, Ont
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49
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Kenny EE, Pe'er I, Karban A, Ozelius L, Mitchell AA, Ng SM, Erazo M, Ostrer H, Abraham C, Abreu MT, Atzmon G, Barzilai N, Brant SR, Bressman S, Burns ER, Chowers Y, Clark LN, Darvasi A, Doheny D, Duerr RH, Eliakim R, Giladi N, Gregersen PK, Hakonarson H, Jones MR, Marder K, McGovern DPB, Mulle J, Orr-Urtreger A, Proctor DD, Pulver A, Rotter JI, Silverberg MS, Ullman T, Warren ST, Waterman M, Zhang W, Bergman A, Mayer L, Katz S, Desnick RJ, Cho JH, Peter I. A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci. PLoS Genet 2012; 8:e1002559. [PMID: 22412388 PMCID: PMC3297573 DOI: 10.1371/journal.pgen.1002559] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Accepted: 01/12/2012] [Indexed: 12/19/2022] Open
Abstract
Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻⁶). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻⁸; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10⁻⁹; OR = 1.16), 8q21.11 (rs12677663, p = 2×10⁻⁸; OR = 1.15), 10q26.3 (rs10734105, p = 3×10⁻⁸; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10⁻⁹; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.
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Affiliation(s)
- Eimear E. Kenny
- Department of Computer Sciences, Columbia University, New York, New York, United States of America
| | - Itsik Pe'er
- Department of Computer Sciences, Columbia University, New York, New York, United States of America
| | - Amir Karban
- Department of Gastroenterology, Rambam Health Care Campus, B. Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Laurie Ozelius
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Adele A. Mitchell
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Sok Meng Ng
- Department of Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut, United States of America
| | - Monica Erazo
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Harry Ostrer
- Department of Pathology, Albert Einstein College of Medicine, New York, New York, United States of America
| | - Clara Abraham
- Department of Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut, United States of America
| | - Maria T. Abreu
- Division of Gastroenterology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Gil Atzmon
- Genetic Core for Longevity, Institute for Aging Research and the Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Nir Barzilai
- Genetic Core for Longevity, Institute for Aging Research and the Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Steven R. Brant
- Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Susan Bressman
- Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, United States of America
- The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Edward R. Burns
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Yehuda Chowers
- Department of Gastroenterology, Rambam Health Care Campus, B. Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Lorraine N. Clark
- Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America
| | - Ariel Darvasi
- The Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Dana Doheny
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Richard H. Duerr
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Rami Eliakim
- Department of Gastroenterology and Hepatology, Sheba Medical Center, Raman Gan, Israel
| | - Nir Giladi
- Department of Neurology, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel
| | - Peter K. Gregersen
- Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, New York, United States of America
| | - Hakon Hakonarson
- Center for Applied Genomics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Michelle R. Jones
- Division of Endocrinology, Diabetes, and Metabolism, Graduate Program in Biomedical Sciences and Translational Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
| | - Karen Marder
- Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
| | - Dermot P. B. McGovern
- Department of Translational Medicine, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
| | - Jennifer Mulle
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Avi Orr-Urtreger
- Genetic Institute, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel
| | - Deborah D. Proctor
- Department of Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut, United States of America
| | - Ann Pulver
- Epidemiology-Genetics Program in Schizophrenia, Bipolar Disorders, and Related Disorders, Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Jerome I. Rotter
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
| | | | - Thomas Ullman
- Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Stephen T. Warren
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America
- Departments of Biochemistry and Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Matti Waterman
- Department of Gastroenterology, Rambam Health Care Campus, B. Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Wei Zhang
- Department of Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut, United States of America
| | - Aviv Bergman
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, New York, New York, United States of America
| | - Lloyd Mayer
- Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Seymour Katz
- Albert Einstein College of Medicine, North Shore University Hospital-Long Island Jewish Hospital Systems, St. Francis Hospital, Great Neck, New York, United States of America
| | - Robert J. Desnick
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Judy H. Cho
- Department of Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut, United States of America
- * E-mail: (JH Cho) (JC); (I Peter) (IP)
| | - Inga Peter
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America
- * E-mail: (JH Cho) (JC); (I Peter) (IP)
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50
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Zintzaras E, Song YB, Zheng WL, Jiang L, Ma WL. Is there evidence to claim or deny association between variants of the multidrug resistance gene (MDR1 or ABCB1) and inflammatory bowel disease? Inflamm Bowel Dis 2012; 18:562-72. [PMID: 21887726 DOI: 10.1002/ibd.21728] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Accepted: 03/16/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a complex disease with a genetic background. Crohn's disease (CD) and ulcerative colitis (UC) are the two main types of IBD. There is indication that variants in the MDR1 gene are associated with development of IBD. However, the 20 published genetic association studies (GAS) for the three most popular variants in the MDR1 gene (C3435T, G2677T/A, and C1236T) have produced inclusive results. METHODS In order to decrease the uncertainty of pooled risk effects and to explore the trend and stability of the risk effects, a meticulous meta-analysis, including cumulative and recursive cumulative meta-analysis, of the GAS related to the MDR1 gene with susceptibility to IBD was conducted. The risk effects were estimated based on the odds ratio (OR) of the allele contrast and the generalized odds ratio (OR(G) ). RESULTS The analysis showed marginal significant association for the C3435T variant in UC: the risk estimate for the allele contrast was OR = 1.11 (1.00-1.22) and OR(G) = 1.12 (1.01-1.27), indicating that a subject with high mutational load has a 12% higher probability of being diseased. The respective cumulative meta-analysis indicated a downward trend of association, as evidence accumulates with the association being significant during the whole published period. The cumulative meta-analysis for the other variants showed lack of any trend of association. However, the recursive cumulative meta-analysis showed that there is no sufficient evidence for denying or claiming an association for all variants. CONCLUSIONS More evidence is needed to draw safe conclusions regarding the association of MDR1 variants and development of IBD.
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Affiliation(s)
- Elias Zintzaras
- Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
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