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Huang K, Zeng T, Koc S, Pettet A, Zhou J, Jain M, Sun D, Ruiz C, Ren H, Howe L, Richardson TG, Cortes A, Aiello K, Branson K, Pfenning A, Engreitz JM, Zhang MJ, Leskovec J. Small-cohort GWAS discovery with AI over massive functional genomics knowledge graph. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.12.03.24318375. [PMID: 39677475 PMCID: PMC11643201 DOI: 10.1101/2024.12.03.24318375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Genome-wide association studies (GWASs) have identified tens of thousands of disease associated variants and provided critical insights into developing effective treatments. However, limited sample sizes have hindered the discovery of variants for uncommon and rare diseases. Here, we introduce KGWAS, a novel geometric deep learning method that leverages a massive functional knowledge graph across variants and genes to improve detection power in small-cohort GWASs significantly. KGWAS assesses the strength of a variant's association to disease based on the aggregate GWAS evidence across molecular elements interacting with the variant within the knowledge graph. Comprehensive simulations and replication experiments showed that, for small sample sizes ( N =1-10K), KGWAS identified up to 100% more statistically significant associations than state-of-the-art GWAS methods and achieved the same statistical power with up to 2.67× fewer samples. We applied KGWAS to 554 uncommon UK Biobank diseases ( N case <5K) and identified 183 more associations (46.9% improvement) than the original GWAS, where the gain further increases to 79.8% for 141 rare diseases (N case <300). The KGWAS-only discoveries are supported by abundant functional evidence, such as rs2155219 (on 11q13) associated with ulcerative colitis potentially via regulating LRRC32 expression in CD4+ regulatory T cells, and rs7312765 (on 12q12) associated with the rare disease myasthenia gravis potentially via regulating PPHLN1 expression in neuron-related cell types. Furthermore, KGWAS consistently improves downstream analyses such as identifying disease-specific network links for interpreting GWAS variants, identifying disease-associated genes, and identifying disease-relevant cell populations. Overall, KGWAS is a flexible and powerful AI model that integrates growing functional genomics data to discover novel variants, genes, cells, and networks, especially valuable for small cohort diseases.
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Bogari NM, Babalghith AO, Azher ZA, Mufti AH, Bouazzaoui A, Banni H, Madkhali AA, Alahmadi A, Allam RM. Impact of rs599839 Polymorphism on Coronary Artery Disease Risk in Saudi Diabetic Patients. DISEASE MARKERS 2024; 2024:8278727. [PMID: 39165561 PMCID: PMC11335421 DOI: 10.1155/2024/8278727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 02/10/2024] [Accepted: 03/15/2024] [Indexed: 08/22/2024]
Abstract
Background Coronary artery diseases may be affected by several genetic and nongenetic factors. Single-nucleotide polymorphism (SNP) rs599839 and type 2 diabetes mellitus (T2DM) can affect the occurrence and severity of coronary artery disease (CAD). Methods Our aim was to investigate how T2DM and the rs599839 variant affected serum lipid levels and the degree of CAD patients' coronary artery stenosis. rs599839 polymorphism genotyping was done on Saudi patients with coronary angiography performed previously. Patients enrolled were divided into group A (360 DM patients), group B (225 DM patients with CAD), and group C (190 healthy volunteers as control). Results Individuals with diabetes and CAD who possessed the GG genotype in rs599839 exhibited markedly reduced means of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG; 224.5, 116.2, and 221.4 versus 251.6, 131.3, and 261.7 mg/dl, p=0.003, 0.007, and 0.025, respectively) than AA genotype. The odds ratio and the confidence interval of 95% for G allele carriers of rs599839 were OR = 0.62, 95% CI: 0.41-0.82, and p=0.003, among diabetic patients with CAD. Conclusions In patients with diabetic CAD, the locus 1p13.3 polymorphism rs599839 was found to be substantially correlated with serum lipid levels. Furthermore, among Saudi patients with diabetes, the G allele of rs599839 variant lowers the CAD risk.
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Affiliation(s)
- Neda M. Bogari
- Department of Medical GeneticsFaculty of MedicineUmm Al-Qura University, Makkah, Saudi Arabia
| | - Ahmad O. Babalghith
- Department of Medical GeneticsFaculty of MedicineUmm Al-Qura University, Makkah, Saudi Arabia
| | - Zohor Asaad Azher
- Department of Medical GeneticsFaculty of MedicineUmm Al-Qura University, Makkah, Saudi Arabia
| | - Ahmad Hasan Mufti
- Department of Medical GeneticsFaculty of MedicineUmm Al-Qura University, Makkah, Saudi Arabia
| | - Abdellatif Bouazzaoui
- Department of Medical GeneticsFaculty of MedicineUmm Al-Qura University, Makkah, Saudi Arabia
- Science and Technology UnitUmm Al Qura University, Makkah, Saudi Arabia
| | - Hussain Banni
- Department of Medical GeneticsFaculty of MedicineUmm Al-Qura University, Makkah, Saudi Arabia
| | - Abdulelah Awaji Madkhali
- Department of Pathology and Laboratory MedicineCytogenetics LabKing Abdulaziz Medical CityMinistry of National Guard Health Affairs, Jeddah, Saudi Arabia
| | - Ahmed Alahmadi
- Department of Pathology and Laboratory MedicineKing Faisal Hospital, Makkah, Saudi Arabia
| | - Reem M. Allam
- Department of Clinical PathologyFaculty of MedicineZagazig University, Zagazig, Egypt
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Walia GK, Panniyammakal J, Agarwal T, Jalal R, Gupta R, Ramakrishnan L, Tandon N, Roy A, Krishnan A, Prabhakaran D. Evaluation of genetic variants related to lipid levels among the North Indian population. Front Genet 2024; 14:1234693. [PMID: 38348409 PMCID: PMC10859749 DOI: 10.3389/fgene.2023.1234693] [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: 06/05/2023] [Accepted: 08/31/2023] [Indexed: 02/15/2024] Open
Abstract
Background: A heavy burden of cardiometabolic conditions on low- and middle-income countries like India that are rapidly undergoing urbanization remains unaddressed. Indians are known to have high levels of triglycerides and low levels of HDL-C along with moderately higher levels of LDL-C. The genome-wide findings from Western populations need to be validated in an Indian context for a better understanding of the underlying etiology of dyslipidemia in India. Objective: We aim to validate 12 genetic variants associated with lipid levels among rural and urban Indian populations and derive unweighted and weighted genetic risk scores (uGRS and wGRS) for lipid levels among the Indian population. Methods: Assuming an additive model of inheritance, linear regression models adjusted for all the possible covariates were run to examine the association between 12 genetic variants and total cholesterol, triglycerides, HDL-C, LDL-C, and VLDL-C among 2,117 rural and urban Indian participants. The combined effect of validated loci was estimated by allelic risk scores, unweighted and weighted by their effect sizes. Results: The wGRS for triglycerides and VLDL-C was derived based on five associated variants (rs174546 at FADS1, rs17482753 at LPL, rs2293889 at TRPS1, rs4148005 at ABCA8, and rs4420638 at APOC1), which was associated with 36.31 mg/dL of elevated triglyceride and VLDL-C levels (β = 0.95, SE = 0.16, p < 0.001). Similarly, every unit of combined risk score (rs2293889 at TRPS1 and rs4147536 at ADH1B) was associated with 40.62 mg/dL of higher total cholesterol (β = 1.01, SE = 0.23, p < 0.001) and 33.97 mg/dL of higher LDL-C (β = 1.03, SE = 0.19, p < 0.001) based on its wGRS (rs2293889 at TRPS1, rs4147536 at ADH1B, rs4420638 at APOC1, and rs660240 at CELSR2). The wGRS derived from five associated variants (rs174546 at FADS1, rs17482753 at LPL, rs4148005 at ABCA8, rs4420638 at APOC1, and rs7832643 at PLEC) was associated with 10.64 mg/dL of lower HDL-C (β = -0.87, SE = 0.14, p < 0.001). Conclusion: We confirm the role of eight genome-wide association study (GWAS) loci related to different lipid levels in the Indian population and demonstrate the combined effect of variants for lipid traits among Indians by deriving the polygenic risk scores. Similar studies among different populations are required to validate the GWAS loci and effect modification of these loci by lifestyle and environmental factors related to urbanization.
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Affiliation(s)
- Gagandeep Kaur Walia
- Public Health Foundation of India, New Delhi, India
- Centre for Chronic Disease Control, New Delhi, India
| | - Jeemon Panniyammakal
- Centre for Chronic Disease Control, New Delhi, India
- Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India
| | - Tripti Agarwal
- Indian Institute of Public Health-Delhi, New Delhi, India
| | - Ruchita Jalal
- Indian Institute of Public Health-Delhi, New Delhi, India
| | - Ruby Gupta
- Centre for Chronic Disease Control, New Delhi, India
| | | | - Nikhil Tandon
- Indian Institute of Public Health-Delhi, New Delhi, India
| | - Ambuj Roy
- Indian Institute of Public Health-Delhi, New Delhi, India
| | - Anand Krishnan
- Indian Institute of Public Health-Delhi, New Delhi, India
| | - Dorairaj Prabhakaran
- Public Health Foundation of India, New Delhi, India
- Centre for Chronic Disease Control, New Delhi, India
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Kumar AHS. Network Proteins of Human Sortilin1, Its Expression and Targetability Using Lycopene. Life (Basel) 2024; 14:137. [PMID: 38255751 PMCID: PMC10817468 DOI: 10.3390/life14010137] [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: 11/30/2023] [Revised: 01/08/2024] [Accepted: 01/16/2024] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Sortilin1 (SORT1) is a ubiquitously expressed transporter involved in sorting or clearing proteins and is pathologically linked to tissue fibrosis and calcification. Targeting SORT1 may have potential clinical efficacy in controlling or reversing cardiovascular fibrosis and/or calcification. Hence, this study assessed the protein-protein network of human SORT1 and its targetability using known nutra-/pharmaceuticals. MATERIAL AND METHODS Network proteins of human SORT1 were identified using the String database, and the affinity of the protein-protein interaction of this network was analysed using Chimera software (Chimera-1.17.3-mac64). The tissue-specific expression profile of SORT1 was evaluated and assessed for enrichment in different cell types, including immune cells. A library of in-house small molecules and currently used therapeutics for cardiovascular diseases were screened using AutoDock Vina to assess the targetability of human SORT1. The concentration affinity (CA) ratio of the small molecules was estimated to assess the clinical feasibility of targeting SORT1. RESULTS IGF2R, NTRK2, GRN and GGA1 were identified as high-affinity interaction networks of SORT1. Of these high-affinity interactions, IGF2R and GRN can be considered relevant networks in regulating tissue fibrosis or the microcalcification process due to their influence on T-cell activation, inflammation, wound repair, and the tissue remodelling process. The tissue cell-type enrichment indicated major expression of SORT1 in adipocytes, specialised epithelial cells, monocytes, cardiomyocytes, and thyroid glandular cells. The binding pocket analysis of human SORT1 showed twelve potential drug interaction sites with varying binding scores (0.86 to 5.83) and probability of interaction (0.004 to 0.304). Five of the drug interaction sites were observed to be targetable at the therapeutically feasible concentration of the small molecules evaluated. Empagliflozin, sitagliptin and lycopene showed a superior affinity and CA ratio compared to established inhibitors of SORT1. CONCLUSION IGF2R and GRN are relevant networks of SORT1, regulating tissue fibrosis or the microcalcification process. SORT1 can be targeted using currently approved small-molecule therapeutics (empagliflozin and sitagliptin) or widely used nutraceuticals (lycopene), which should be evaluated in a randomised clinical trial to assess their efficacy in reducing the cardiac/vascular microcalcification process.
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Affiliation(s)
- Arun H S Kumar
- Stemcology, School of Veterinary Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland
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Mitok KA, Schueler KL, King SM, Orr J, Ryan KA, Keller MP, Krauss RM, Mitchell BD, Shuldiner AR, Attie AD. Missense variants in SORT1 are associated with LDL-C in an Amish population. J Lipid Res 2023; 64:100468. [PMID: 37913995 PMCID: PMC10711479 DOI: 10.1016/j.jlr.2023.100468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/23/2023] [Accepted: 10/26/2023] [Indexed: 11/03/2023] Open
Abstract
Common noncoding variants at the human 1p13.3 locus associated with SORT1 expression are among those most strongly associated with low-density lipoprotein cholesterol (LDL-C) in human genome-wide association studies. However, validation studies in mice and cell lines have produced variable results regarding the directionality of the effect of SORT1 on LDL-C. This, together with the fact that the 1p13.3 variants are associated with expression of several genes, has raised the question of whether SORT1 is the causal gene at this locus. Using whole exome sequencing in members of an Amish population, we identified coding variants in SORT1 that are associated with increased (rs141749679, K302E) and decreased (rs149456022, Q225H) LDL-C. Further, analysis of plasma lipoprotein particle subclasses by ion mobility in a subset of rs141749679 (K302E) carriers revealed higher levels of large LDL particles compared to noncarriers. In contrast to the effect of these variants in the Amish, the sortilin K302E mutation introduced into a C57BL/6J mouse via CRISPR/Cas9 resulted in decreased non-high-density lipoprotein cholesterol, and the sortilin Q225H mutation did not alter cholesterol levels in mice. This is indicative of different effects of these mutations on cholesterol metabolism in the two species. To our knowledge, this is the first evidence that naturally occurring coding variants in SORT1 are associated with LDL-C, thus supporting SORT1 as the gene responsible for the association of the 1p13.3 locus with LDL-C.
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Affiliation(s)
- Kelly A Mitok
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Kathryn L Schueler
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Sarah M King
- Department of Pediatrics, University of California-San Francisco, San Francisco, CA, USA
| | - Joseph Orr
- Department of Pediatrics, University of California-San Francisco, San Francisco, CA, USA
| | - Kathleen A Ryan
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Mark P Keller
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Ronald M Krauss
- Department of Pediatrics, University of California-San Francisco, San Francisco, CA, USA
| | - Braxton D Mitchell
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Alan R Shuldiner
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Regeneron Genetics Center, Tarrytown, NY, USA
| | - Alan D Attie
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
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Ji Y, Temprano-Sagrera G, Holle LA, Bebo A, Brody JA, Le NQ, Kangro K, Brown MR, Martinez-Perez A, Sitlani CM, Suchon P, Kleber ME, Emmert DB, Ozel AB, Dobson DA, Tang W, Llobet D, Tracy RP, Deleuze JF, Delgado GE, Gögele M, Wiggins KL, Souto JC, Pankow JS, Taylor KD, Trégouët DA, Moissl AP, Fuchsberger C, Rosendaal FR, Morrison AC, Soria JM, Cushman M, Morange PE, März W, Hicks AA, Desch KC, Johnson AD, de Vries PS, CHARGE Consortium Hemostasis Working Group, INVENT Consortium, Wolberg AS, Smith NL, Sabater-Lleal M. Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels. Arterioscler Thromb Vasc Biol 2023; 43:e254-e269. [PMID: 37128921 PMCID: PMC10330350 DOI: 10.1161/atvbaha.122.318213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 04/13/2023] [Indexed: 05/03/2023]
Abstract
BACKGROUND Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. METHODS Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. RESULTS Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. CONCLUSIONS The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.
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Affiliation(s)
- Yuekai Ji
- Cardiovascular Division, Department of Medicine, University of Minnesota, MN, USA
| | - Gerard Temprano-Sagrera
- Unit of genomics of Complex Disease, Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
| | - Lori A Holle
- Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, NC, USA
| | - Allison Bebo
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, TX, USA
| | | | - Ngoc-Quynh Le
- Unit of genomics of Complex Disease, Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
| | - Kadri Kangro
- Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, NC, USA
| | - Michael R Brown
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, TX, USA
| | - Angel Martinez-Perez
- Unit of genomics of Complex Disease, Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
| | - Colleen M Sitlani
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, WA, USA
| | - Pierre Suchon
- C2VN, INSERM, INRAE, Aix Marseille Univ, France
- Laboratory of Haematology, La Timone Hospital, France
| | - Marcus E Kleber
- SYNLAB MVZ für Humangenetik Mannheim, Germany
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Germany
| | - David B Emmert
- Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Italy
| | - Ayse Bilge Ozel
- Department of Human Genetics, University of Michigan, C.S. Mott Children’s Hospital, MI, USA
| | - Dre’Von A Dobson
- Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, NC, USA
| | - Weihong Tang
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, MN, USA
| | - Dolors Llobet
- Unit of Thrombosis and Hemostasis, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Russell P Tracy
- Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, VT, USA
| | - Jean-François Deleuze
- Centre National de Recherche en Génomique Humaine, CEA, France
- Centre d’Etude du Polymorphisme Humain, Fondation Jean Dausset, France
- Laboratory of Excellence on Medical Genomics (GenMed), France
| | - Graciela E Delgado
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Germany
| | - Martin Gögele
- Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Italy
| | | | - Juan Carlos Souto
- Unit of genomics of Complex Disease, Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- Unit of Thrombosis and Hemostasis, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - James S Pankow
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, MN, USA
| | - Kent D Taylor
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, CA, USA
| | - David-Alexandre Trégouët
- Laboratory of Excellence on Medical Genomics (GenMed), France
- INSERM UMR 1219, Bordeaux Population Health Research Center, France
| | - Angela P Moissl
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Germany
- Institute of Nutritional Sciences, Friedrich Schiller University Jena, Germany
- Competence Cluster for Nutrition and Cardiovascular Health(nutriCARD) Halle-Jena-Leipzig, Germany
| | - Christian Fuchsberger
- Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Italy
| | - Frits R Rosendaal
- Department of Clinical Epidemiology, Leiden University Medical Center, the Netherlands
| | - Alanna C Morrison
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, TX, USA
| | - Jose Manuel Soria
- Unit of genomics of Complex Disease, Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
| | - Mary Cushman
- Larner College of Medicine, University of Vermont, VT, USA
| | - Pierre-Emmanuel Morange
- C2VN, INSERM, INRAE, Aix Marseille Univ, France
- Laboratory of Haematology, La Timone Hospital, France
| | - Winfried März
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Germany
- Synlab Academy, Synlab Holding Deutschland GmbH, Germany
| | - Andrew A Hicks
- Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Italy
| | - Karl C Desch
- Department of Pediatrics, University of Michigan, C.S. Mott Children’s Hospital, MI, USA
| | - Andrew D Johnson
- National Heart Lung and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, MA, USA
| | - Paul S de Vries
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, TX, USA
| | | | | | - Alisa S Wolberg
- Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, NC, USA
| | - Nicholas L Smith
- Department of Epidemiology, University of Washington, WA, USA
- Kaiser Permanente Washington Health Research Institute, Kaiser Permanente, WA, USA
- Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, WA, USA
| | - Maria Sabater-Lleal
- Unit of genomics of Complex Disease, Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden
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Pan H, Guo Z, Lv P, Hu K, Wu T, Lin Z, Xue Y, Zhang Y, Guo Z. Proline/serine-rich coiled-coil protein 1 inhibits macrophage inflammation and delays atherosclerotic progression by binding to Annexin A2. Clin Transl Med 2023; 13:e1220. [PMID: 36932468 PMCID: PMC10023832 DOI: 10.1002/ctm2.1220] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 02/21/2023] [Accepted: 02/28/2023] [Indexed: 03/19/2023] Open
Abstract
BACKGROUND Atherosclerosis (AS), the main pathological basis of life-threatening cardiovascular disease, is essentially caused by chronic macrophage inflammation. Overexpression of proline/serine-rich coiled-coil protein 1 (PSRC1) reduces macrophage inflammatory responses and delays AS development. However, the exact mechanism of PSRC1 is unclear. METHODS Proteins interacting with PSRC1 were screened by proteomics in RAW264.7 cells, followed by RT-qPCR, immunoprecipitation and immunofluorescence to explore the specific mechanistic pathways affecting inflammation. CRISPR-Cas9 constructs for PSRC1-/- ApoE-/- (DKO) mice and high-fat diet-fed ApoE-/- and DKO mice were used for AS models for in vivo experiments. Upstream transcription factors of PSRC1 were predicted by ATAC-seq, ChIP-seq and UCSC, and the regulatory mechanism was verified by ChIP-qPCR and dual luciferase assays. Peripheral blood serum and monocytes were collected from coronary artery disease (CAD) patients and non-CAD patients. RESULTS Increased binding of ANXA2 to PSRC1 in macrophages under oxidized low-density lipoprotein stimulation and decreased release of ANXA2 to the extracellular compartment were observed. Knockdown of ANXA2 in AS model mice delayed AS progression. Knockdown of ANXA2 in DKO mice reversed the AS-promoting effect of PSRC1 knockdown. Mechanistically, ANXA2 promotes STAT3 phosphorylation, which in turn promotes inflammatory responses. In addition, SP1 is a PSRC1 upstream repressive transcription factor, and the SP1 inhibitor mithramycin (Mith) elevated PSRC1 expression and exerted anti-AS effects in AS model mice. Patients with CAD had considerably greater serum levels of ANXA2 than those without CAD, and Mith reduced the secretion of ANXA2 in peripheral blood monocytes of CAD patients. CONCLUSION In macrophages, PSRC1 can interact with ANXA2 to inhibit its extracellular release and delay AS development. SP1 is an upstream transcription factor of PSRC1 and inhibits the transcription of PSRC1. The SP1 inhibitor Mith can elevate PSRC1 levels and slow AS progression while reducing ANXA2 release from monocytes in CAD patients. Mith is expected to be a new agent for AS treatment.
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Affiliation(s)
- Hangyu Pan
- Department of CardiologyState Key Laboratory of Organ Failure ResearchNanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Zhongzhou Guo
- Department of PharmacyZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Ping Lv
- Department of Cardiovascular SurgeryNanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Kexin Hu
- Department of CardiologyState Key Laboratory of Organ Failure ResearchNanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Tongwei Wu
- Department of Medicine UltrasonicsNanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Zixiang Lin
- Department of CardiologyShenzhen HospitalHuazhong University of Science and Technology UnionShenzhenChina
| | - Yazhi Xue
- Department of General PracticeNanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Yanan Zhang
- Department of CardiologyState Key Laboratory of Organ Failure ResearchNanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Zhigang Guo
- Department of CardiologyHuiqiao Medical CenterNanfang HospitalSouthern Medical UniversityGuangzhouChina
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8
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Association between Genetic Variants of CELSR2-PSRC1-SORT1 and Cardiovascular Diseases: A Systematic Review and Meta-Analysis. J Cardiovasc Dev Dis 2023; 10:jcdd10030091. [PMID: 36975855 PMCID: PMC10056735 DOI: 10.3390/jcdd10030091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 02/11/2023] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
A cluster of three genes CELSR2, PSRC1, and SORT1 has been associated with cardiovascular diseases. Thus, the aim of this study was (i) to perform a systematic review and updated meta-analysis of the association of three polymorphisms (rs646776, rs599839, and rs464218) of this cluster with cardiovascular diseases, and (ii) to explore by PheWAS signals of the three SNPs in cardiovascular diseases and to evaluate the effect of rs599839 with tissue expression by in silico tools. Three electronic databases were searched to identify eligible studies. The meta-analysis showed that the rs599839 (allelic OR 1.19, 95% CI 1.13–1.26, dominant OR 1.22, 95% CI 1.06–1.39, recessive OR 1.23, 95% CI 1.15–1.32), rs646776 (allelic OR 1.46, 95% CI 1.17–1.82) polymorphisms showed an increased risk for cardiovascular diseases. PheWas analysis showed associations with coronary artery disease and total cholesterol. Our results suggest a possible involvement of the CELSR2-PSRC1-SORT1 cluster variants in the risk association of cardiovascular diseases, particularly coronary artery disease.
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Kim Y, Chi YY, Shen J, Zou F. Robust genetic model-based SNP-set association test using CauchyGM. BIOINFORMATICS (OXFORD, ENGLAND) 2023; 39:6831090. [PMID: 36383169 DOI: 10.1093/bioinformatics/btac728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 10/26/2022] [Accepted: 11/15/2022] [Indexed: 11/17/2022]
Abstract
MOTIVATION Association testing on genome-wide association studies (GWAS) data is commonly performed under a single (mostly additive) genetic model framework. However, the underlying true genetic mechanisms are often unknown in practice for most complex traits. When the employed inheritance model deviates from the underlying model, statistical power may be reduced. To overcome this challenge, an integrative association test that directly infers the underlying genetic model from GWAS data has previously been proposed for single-SNP analysis. RESULTS In this article, we propose a Cauchy combination Genetic Model-based association test (CauchyGM) under a generalized linear model framework for SNP-set level analysis. CauchyGM does not require prior knowledge on the underlying inheritance pattern of each SNP. It performs a score test that first estimates an individual P-value of each SNP in an SNP-set with both minor allele frequency (MAF) > 1% and three genotypes and further aggregates the rest SNPs using SKAT. CauchyGM then combines the correlated P-values across multiple SNPs and different genetic models within the set using Cauchy Combination Test. To further accommodate both sparse and dense signal patterns, we also propose an omnibus association test (CauchyGM-O) by combining CauchyGM with SKAT and the burden test. Our extensive simulations show that both CauchyGM and CauchyGM-O maintain the type I error well at the genome-wide significance level and provide substantial power improvement compared to existing methods. We apply our methods to a pharmacogenomic GWAS data from a large cardiovascular randomized clinical trial. Both CauchyGM and CauchyGM-O identify several novel genome-wide significant genes. AVAILABILITY AND IMPLEMENTATION The R package CauchyGM is publicly available on github: https://github.com/ykim03517/CauchyGM. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Yeonil Kim
- Biostatistics and Research Decision Sciences, Merck & Co., Inc., Rahway, NJ 07065, USA
| | - Yueh-Yun Chi
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Judong Shen
- Biostatistics and Research Decision Sciences, Merck & Co., Inc., Rahway, NJ 07065, USA
| | - Fei Zou
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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10
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Mitok KA, Keller MP, Attie AD. Sorting through the extensive and confusing roles of sortilin in metabolic disease. J Lipid Res 2022; 63:100243. [PMID: 35724703 PMCID: PMC9356209 DOI: 10.1016/j.jlr.2022.100243] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 06/10/2022] [Accepted: 06/13/2022] [Indexed: 01/06/2023] Open
Abstract
Sortilin is a post-Golgi trafficking receptor homologous to the yeast vacuolar protein sorting receptor 10 (VPS10). The VPS10 motif on sortilin is a 10-bladed β-propeller structure capable of binding more than 50 proteins, covering a wide range of biological functions including lipid and lipoprotein metabolism, neuronal growth and death, inflammation, and lysosomal degradation. Sortilin has a complex cellular trafficking itinerary, where it functions as a receptor in the trans-Golgi network, endosomes, secretory vesicles, multivesicular bodies, and at the cell surface. In addition, sortilin is associated with hypercholesterolemia, Alzheimer's disease, prion diseases, Parkinson's disease, and inflammation syndromes. The 1p13.3 locus containing SORT1, the gene encoding sortilin, carries the strongest association with LDL-C of all loci in human genome-wide association studies. However, the mechanism by which sortilin influences LDL-C is unclear. Here, we review the role sortilin plays in cardiovascular and metabolic diseases and describe in detail the large and often contradictory literature on the role of sortilin in the regulation of LDL-C levels.
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Affiliation(s)
- Kelly A Mitok
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Mark P Keller
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Alan D Attie
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
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11
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Deficiency of proline/serine-rich coiled-coil protein 1 (PSRC1) accelerates trimethylamine N-oxide-induced atherosclerosis in ApoE -/- mice. J Mol Cell Cardiol 2022; 170:60-74. [PMID: 35690006 DOI: 10.1016/j.yjmcc.2022.05.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/03/2022] [Accepted: 05/30/2022] [Indexed: 02/07/2023]
Abstract
AIMS The main therapeutic strategies for coronary artery disease (CAD) are mainly based on the correction of abnormal cholesterol levels; however, residual risks remain. The newly proven gut microbial metabolite trimethylamine N-oxide (TMAO) linked with CAD has broadened our horizons. In this study, we determined the role of proline/serine-rich coiled-coil protein 1 (PSRC1) in TMAO-driven atherosclerosis. METHODS AND RESULTS We first analyzed the levels of TMAO and PSRC1 in patients with or without atherosclerosis with a target LDL-C < 1.8 mmol/L. Plasma TMAO levels were increased and negatively associated with decreased PSRC1 in peripheral blood mononuclear cells. Animals and in vitro studies showed that TMAO inhibited macrophage PSRC1 expression due to DNA hypermethylation of CpG islands. ApoE-/- mice fed a choline-supplemented diet exhibited reduced PSRC1 expression accompanied by increased atherosclerotic lesions and plasma TMAO levels. We further deleted PSRC1 in apoE-/- mice and PSRC1 deficiency significantly accelerated choline-induced atherogenesis, characterized by increased macrophage infiltration, foam cell formation and M1 macrophage polarization. Mechanistically, we overexpressed and knocked out PSRC1 in cultured macrophages to explore the mechanisms underlying TMAO-induced cholesterol accumulation and inflammation. PSRC1 deletion impaired reverse cholesterol transport and enhanced cholesterol uptake and inflammation, while PSRC1 overexpression rescued the proatherogenic phenotype observed in TMAO-stimulated macrophages, which was partially attributed to sulfotransferase 2B1b (SULT2B1b) inhibition. CONCLUSIONS Herein, clinical data provide evidence that TMAO may participate in the development of CAD beyond well-controlled LDL-C levels. Our work also suggests that PSRC1 is a negative regulator mediating the unfavorable effects of TMAO-containing diets. Therefore, PSRC1 overexpression and reduced choline consumption may further alleviate atherosclerosis.
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Luo T, Guo Z, Liu D, Guo Z, Wu Q, Li Q, Lin R, Chen P, Ou C, Chen M. Deficiency of PSRC1 accelerates atherosclerosis by increasing TMAO production via manipulating gut microbiota and flavin monooxygenase 3. Gut Microbes 2022; 14:2077602. [PMID: 35613310 PMCID: PMC9135421 DOI: 10.1080/19490976.2022.2077602] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Maladaptive inflammatory and immune responses are responsible for intestinal barrier integrity and function dysregulation. Proline/serine-rich coiled-coil protein 1 (PSRC1) critically contributes to the immune system, but direct data on the gut microbiota and the microbial metabolite trimethylamine N-oxide (TMAO) are lacking. Here, we investigated the impact of PSRC1 deletion on TMAO generation and atherosclerosis. We first found that PSRC1 deletion in apoE-/- mice accelerated atherosclerotic plaque formation, and then the gut microbiota and metabolites were detected using metagenomics and untargeted metabolomics. Our results showed that PSRC1 deficiency enriched trimethylamine (TMA)-producing bacteria and functional potential for TMA synthesis and accordingly enhanced plasma betaine and TMAO production. Furthermore, PSRC1 deficiency resulted in a proinflammatory colonic phenotype that was significantly associated with the dysregulated bacteria. Unexpectedly, hepatic RNA-seq indicated upregulated flavin monooxygenase 3 (FMO3) expression following PSRC1 knockout. Mechanistically, PSRC1 overexpression inhibited FMO3 expression in vitro, while an ERα inhibitor rescued the downregulation. Consistently, PSRC1-knockout mice exhibited higher plasma TMAO levels with a choline-supplemented diet, which was gut microbiota dependent, as evidenced by antibiotic treatment. To investigate the role of dysbiosis induced by PSRC1 deletion in atherogenesis, apoE-/- mice were transplanted with the fecal microbiota from either apoE-/- or PSRC1-/-apoE-/- donor mice. Mice that received PSRC1-knockout mouse feces showed an elevation in TMAO levels, as well as plaque lipid deposition and macrophage accumulation, which were accompanied by increased plasma lipid levels and impaired hepatic cholesterol transport. Overall, we identified PSRC1 as an atherosclerosis-protective factor, at least in part, attributable to its regulation of TMAO generation via a multistep pathway. Thus, PSRC1 holds great potential for manipulating the gut microbiome and alleviating atherosclerosis.
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Affiliation(s)
- Tiantian Luo
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China,Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Lab of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhigang Guo
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Dan Liu
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Lab of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhongzhou Guo
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Qiao Wu
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qinxian Li
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Lab of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rongzhan Lin
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Lab of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Peier Chen
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China
| | - Caiwen Ou
- Guangdong Provincial Key Laboratory of Shock and Microcirculation, Dongguan Hospital of Southern Medical University, Southern Medical University, Guangzhou, China,CONTACT Caiwen Ou Dongguan Hospital of Southern Medical University, Southern Medical University, Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China
| | - Minsheng Chen
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China,Minsheng Chen Laboratory of Heart Center and Department of Cardiology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong, 510260, P.R. China
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Powerful and robust inference of complex phenotypes' causal genes with dependent expression quantitative loci by a median-based Mendelian randomization. Am J Hum Genet 2022; 109:838-856. [PMID: 35460606 DOI: 10.1016/j.ajhg.2022.04.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 04/04/2022] [Indexed: 11/22/2022] Open
Abstract
Isolating the causal genes from numerous genetic association signals in genome-wide association studies (GWASs) of complex phenotypes remains an open and challenging question. In the present study, we proposed a statistical approach, the effective-median-based Mendelian randomization (MR) framework, for inferring the causal genes of complex phenotypes with the GWAS summary statistics (named EMIC). The effective-median method solved the high false-positive issue in the existing MR methods due to either correlation among instrumental variables or noises in approximated linkage disequilibrium (LD). EMIC can further perform a pleiotropy fine-mapping analysis to remove possible false-positive estimates. With the usage of multiple cis-expression quantitative trait loci (eQTLs), EMIC was also more powerful than the alternative methods for the causal gene inference in the simulated datasets. Furthermore, EMIC rediscovered many known causal genes of complex phenotypes (schizophrenia, bipolar disorder, and total cholesterol) and reported many new and promising candidate causal genes. In sum, this study provided an efficient solution to discriminate the candidate causal genes from vast amounts of GWAS signals with eQTLs. EMIC has been implemented in our integrative software platform KGGSEE.
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14
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Li L, Chen Z, von Scheidt M, Li S, Steiner A, Güldener U, Koplev S, Ma A, Hao K, Pan C, Lusis AJ, Pang S, Kessler T, Ermel R, Sukhavasi K, Ruusalepp A, Gagneur J, Erdmann J, Kovacic JC, Björkegren JLM, Schunkert H. Transcriptome-wide association study of coronary artery disease identifies novel susceptibility genes. Basic Res Cardiol 2022; 117:6. [PMID: 35175464 PMCID: PMC8852935 DOI: 10.1007/s00395-022-00917-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 01/18/2022] [Accepted: 02/01/2022] [Indexed: 01/31/2023]
Abstract
The majority of risk loci identified by genome-wide association studies (GWAS) are in non-coding regions, hampering their functional interpretation. Instead, transcriptome-wide association studies (TWAS) identify gene-trait associations, which can be used to prioritize candidate genes in disease-relevant tissue(s). Here, we aimed to systematically identify susceptibility genes for coronary artery disease (CAD) by TWAS. We trained prediction models of nine CAD-relevant tissues using EpiXcan based on two genetics-of-gene-expression panels, the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) and the Genotype-Tissue Expression (GTEx). Based on these prediction models, we imputed gene expression of respective tissues from individual-level genotype data on 37,997 CAD cases and 42,854 controls for the subsequent gene-trait association analysis. Transcriptome-wide significant association (i.e. P < 3.85e-6) was observed for 114 genes. Of these, 96 resided within previously identified GWAS risk loci and 18 were novel. Stepwise analyses were performed to study their plausibility, biological function, and pathogenicity in CAD, including analyses for colocalization, damaging mutations, pathway enrichment, phenome-wide associations with human data and expression-traits correlations using mouse data. Finally, CRISPR/Cas9-based gene knockdown of two newly identified TWAS genes, RGS19 and KPTN, in a human hepatocyte cell line resulted in reduced secretion of APOB100 and lipids in the cell culture medium. Our CAD TWAS work (i) prioritized candidate causal genes at known GWAS loci, (ii) identified 18 novel genes to be associated with CAD, and iii) suggested potential tissues and pathways of action for these TWAS CAD genes.
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Affiliation(s)
- Ling Li
- Department of Cardiology, German Heart Center Munich, Technical University Munich, Lazarettstraße 36, 80636, Munich, Germany
- Fakultät für Informatik, Technische Universität München, Munich, Germany
- Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Zhifen Chen
- Department of Cardiology, German Heart Center Munich, Technical University Munich, Lazarettstraße 36, 80636, Munich, Germany
- Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Moritz von Scheidt
- Department of Cardiology, German Heart Center Munich, Technical University Munich, Lazarettstraße 36, 80636, Munich, Germany
- Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Shuangyue Li
- Department of Cardiology, German Heart Center Munich, Technical University Munich, Lazarettstraße 36, 80636, Munich, Germany
- Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Andrea Steiner
- Department of Cardiology, German Heart Center Munich, Technical University Munich, Lazarettstraße 36, 80636, Munich, Germany
- Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Ulrich Güldener
- Department of Cardiology, German Heart Center Munich, Technical University Munich, Lazarettstraße 36, 80636, Munich, Germany
- Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Simon Koplev
- Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029-6574, USA
| | - Angela Ma
- Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029-6574, USA
| | - Ke Hao
- Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029-6574, USA
| | - Calvin Pan
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Aldons J Lusis
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Shichao Pang
- Department of Cardiology, German Heart Center Munich, Technical University Munich, Lazarettstraße 36, 80636, Munich, Germany
- Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Thorsten Kessler
- Department of Cardiology, German Heart Center Munich, Technical University Munich, Lazarettstraße 36, 80636, Munich, Germany
- Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Raili Ermel
- Department of Cardiac Surgery, The Heart Clinic, Tartu University Hospital, Tartu, Estonia
| | - Katyayani Sukhavasi
- Department of Cardiac Surgery, The Heart Clinic, Tartu University Hospital, Tartu, Estonia
| | - Arno Ruusalepp
- Department of Cardiac Surgery, The Heart Clinic, Tartu University Hospital, Tartu, Estonia
- Clinical Gene Networks AB, Stockholm, Sweden
| | - Julien Gagneur
- Fakultät für Informatik, Technische Universität München, Munich, Germany
| | - Jeanette Erdmann
- DZHK (German Research Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany
- Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
| | - Jason C Kovacic
- Victor Chang Cardiac Research Institute, Darlinghurst, Australia
- St Vincent's Clinical School, University of New South Wales, Sydney, Australia
- Icahn School of Medicine at Mount Sinai, Cardiovascular Research Institute, New York, NY, 10029-6574, USA
| | - Johan L M Björkegren
- Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029-6574, USA
- Clinical Gene Networks AB, Stockholm, Sweden
- Department of Medicine, Huddinge, Karolinska Institutet, Karolinska Universitetssjukhuset, Stockholm, Sweden
| | - Heribert Schunkert
- Department of Cardiology, German Heart Center Munich, Technical University Munich, Lazarettstraße 36, 80636, Munich, Germany.
- Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
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15
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Khorrami MS, Sadabadi F, Pasdar A, Safarian-Bana H, Amerizadeh F, Esmaeily H, Moohebati M, Heidari-Bakavoli A, Ferns G, Ghayour-Mobarhan M, Avan A. A Genetic Variant in Proline and Serine Rich Coiled-Coil 1 Gene Is Associated with the Risk of Cardiovascular Disease. Rep Biochem Mol Biol 2022; 10:653-663. [PMID: 35291603 PMCID: PMC8903358 DOI: 10.52547/rbmb.10.4.653] [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: 07/28/2021] [Accepted: 09/06/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Cardiovascular disease is one of the most common causes of morbidity and mortality worldwide. The Proline and Serine Rich Coiled-Coil 1 gene in 1p13.3 locus has been reported to be associated with low density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD). The objective of this study was to investigate the association between the rs599839 polymorphism of the Proline and Serine Rich Coiled-Coil 1 (PSRC1) gene with CVD outcomes in a population sample recruited as part of the Mashhad-Stroke and Heart-Atherosclerotic-Disorders (MASHAD) cohort. METHODS Five hundred and nine individuals who had an average follow-up period of 10 years were enrolled as part of the MASHAD cohort. DNA was extracted and genotyped using the TaqMan-real-time-PCR based method. RESULTS The study found individuals with GA/GG genotypes were at a higher risk of CVDs (OR= 4.7; 95% CI, 2.5-8.7; p< 0.001) in comparison to those with AA genotype; however, the result was not significant for GG genotype data. CONCLUSION The results suggest that the GA/GG genotypes of the PSRC1gene locus were at increased risk of CVD in a representative population-based cohort, demonstrating further functional analysis to discover the value of emerging marker as a risk stratification biomarker to recognize high risk cases.
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Affiliation(s)
- Mohammad Sadegh Khorrami
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Metabolic Syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Fatemeh Sadabadi
- Metabolic Syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Alireza Pasdar
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Hamide Safarian-Bana
- Metabolic Syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Forouzan Amerizadeh
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Habibollah Esmaeily
- Metabolic Syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Epidemiology and Biostatistics, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mohsen Moohebati
- Metabolic Syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | | | - Gordon Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex, UK.
| | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amir Avan
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Metabolic Syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
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16
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Schaid DJ, Dikilitas O, Sinnwell JP, Kullo IJ. Penalized mediation models for multivariate data. Genet Epidemiol 2021; 46:32-50. [PMID: 34664742 DOI: 10.1002/gepi.22433] [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: 05/30/2021] [Revised: 08/04/2021] [Accepted: 10/04/2021] [Indexed: 11/11/2022]
Abstract
Statistical methods to integrate multiple layers of data, from exposures to intermediate traits to outcome variables, are needed to guide interpretation of complex data sets for which variables are likely contributing in a causal pathway from exposure to outcome. Statistical mediation analysis based on structural equation models provide a general modeling framework, yet they can be difficult to apply to high-dimensional data and they are not automated to select the best fitting model. To overcome these limitations, we developed novel algorithms and software to simultaneously evaluate multiple exposure variables, multiple intermediate traits, and multiple outcome variables. Our penalized mediation models are computationally efficient and simulations demonstrate that they produce reliable results for large data sets. Application of our methods to a study of vascular disease demonstrates their utility to identify novel direct effects of single-nucleotide polymorphisms (SNPs) on coronary heart disease and peripheral artery disease, while disentangling the effects of SNPs on the intermediate risk factors including lipids, cigarette smoking, systolic blood pressure, and type 2 diabetes.
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Affiliation(s)
- Daniel J Schaid
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Ozan Dikilitas
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Jason P Sinnwell
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Iftikhar J Kullo
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
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17
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Tan J, Che Y, Liu Y, Hu J, Wang W, Hu L, Zhou Q, Wang H, Li J. CELSR2 deficiency suppresses lipid accumulation in hepatocyte by impairing the UPR and elevating ROS level. FASEB J 2021; 35:e21908. [PMID: 34478580 DOI: 10.1096/fj.202100786rr] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/21/2021] [Accepted: 08/24/2021] [Indexed: 01/06/2023]
Abstract
Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2), a mammalian orthologue of drosophila flamingo, belongs to the cadherin subfamily. CELSR2 mainly function in neural development and cilium polarity. Recent studies showed that the CELSR2 gene is related to many human diseases, including coronary artery disease, idiopathic scoliosis, and cancer. Genome-Wide Association Studies data showed that SNP in the CELSR2-PSRC1-SORT1 gene loci has a strong association with circulating lipid levels and coronary artery disease. However, the function and underlying mechanism of CELSR2 in hepatic lipid metabolism remain unknown. Here, we found that CELSR2 expression is decreased in the liver of NAFLD/NASH patients and db/db mice. Depletion of CELSR2 significantly decreased the lipid accumulation in hepatocytes by suppressing the expression of lipid synthesis enzymes. Moreover, CELSR2 deficiency impaired the physiological unfolded protein response (UPR), which damages the ER homeostasis, and elevates the reactive oxygen species (ROS) level by decreasing the antioxidant expression. Scavenging of ROS by N-acetylcysteine treatment could restore the decreased lipid accumulation of CELSR2 knockdown cells. Furthermore, CELSR2 loss impaired cell survival by suppressing cell proliferation and promoting apoptosis. Our results uncovered a new role of CELSR2 in regulating lipid homeostasis and UPR, suggesting CELSR2 may be a new therapeutic target for non-alcoholic fatty liver disease.
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Affiliation(s)
- Junyang Tan
- Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China.,The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, China
| | - Yaping Che
- The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, China
| | - Yanyan Liu
- The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, China
| | - Jiaqiao Hu
- The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, China
| | - Wenjun Wang
- Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China.,The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, China.,The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Liubing Hu
- The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, China
| | - Qinghua Zhou
- Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China.,The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, China.,The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Hao Wang
- The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Jianshuang Li
- Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China.,The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, China
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18
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Møller PL, Rohde PD, Winther S, Breining P, Nissen L, Nykjaer A, Bøttcher M, Nyegaard M, Kjolby M. Sortilin as a Biomarker for Cardiovascular Disease Revisited. Front Cardiovasc Med 2021; 8:652584. [PMID: 33937362 PMCID: PMC8085299 DOI: 10.3389/fcvm.2021.652584] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/22/2021] [Indexed: 11/13/2022] Open
Abstract
Genetic variants in the genomic region containing SORT1 (encoding the protein sortilin) are strongly associated with cholesterol levels and the risk of coronary artery disease (CAD). Circulating sortilin has therefore been proposed as a potential biomarker for cardiovascular disease. Multiple studies have reported association between plasma sortilin levels and cardiovascular outcomes. However, the findings are not consistent across studies, and most studies have small sample sizes. The aim of this study was to evaluate sortilin as a biomarker for CAD in a well-characterized cohort with symptoms suggestive of CAD. In total, we enrolled 1,173 patients with suspected stable CAD referred to coronary computed tomography angiography. Sortilin was measured in plasma using two different technologies for quantifying circulating sortilin: a custom-made enzyme-linked immunosorbent assay (ELISA) and OLINK Cardiovascular Panel II. We found a relative poor correlation between the two methods (correlation coefficient = 0.21). In addition, genotyping and whole-genome sequencing were performed on all patients. By whole-genome regression analysis of sortilin levels measured with ELISA and OLINK, two independent cis protein quantitative trait loci (pQTL) on chromosome 1p13.3 were identified, with one of them being a well-established risk locus for CAD. Incorporating rare genetic variants from whole-genome sequence data did not identify any additional pQTLs for plasma sortilin. None of the traditional CAD risk factors, such as sex, age, smoking, and statin use, were associated with plasma sortilin levels. Furthermore, there was no association between circulating sortilin levels and coronary artery calcium score (CACS) or disease severity. Sortilin did not improve discrimination of obstructive CAD, when added to a clinical pretest probability (PTP) model for CAD. Overall, our results indicate that studies using different methodologies for measuring circulating sortilin should be compared with caution. In conclusion, the well-known SORT1 risk locus for CAD is linked to lower sortilin levels in circulation, measured with ELISA; however, the effect sizes are too small for sortilin to be a useful biomarker for CAD in a clinical setting of low- to intermediate-risk chest-pain patients.
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Affiliation(s)
| | - Palle D. Rohde
- Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark
| | - Simon Winther
- Department of Cardiology, Gødstrup Hospital, NIDO, Herning, Denmark
| | - Peter Breining
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- PROMEMO and DANDRITE, Aarhus University, Aarhus, Denmark
| | - Louise Nissen
- Department of Cardiology, Gødstrup Hospital, NIDO, Herning, Denmark
| | - Anders Nykjaer
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- PROMEMO and DANDRITE, Aarhus University, Aarhus, Denmark
| | - Morten Bøttcher
- Department of Cardiology, Gødstrup Hospital, NIDO, Herning, Denmark
| | - Mette Nyegaard
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Mads Kjolby
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- PROMEMO and DANDRITE, Aarhus University, Aarhus, Denmark
- Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
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19
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The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients. Cancers (Basel) 2021; 13:cancers13081783. [PMID: 33917919 PMCID: PMC8068289 DOI: 10.3390/cancers13081783] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 03/31/2021] [Accepted: 04/01/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary Dyslipidemia is a hallmark of nonalcoholic fatty liver disease (NAFLD) and the rs599839 variant in the CELSR2-PSRC1-SORT1 genetic cluster, has been associated with a protection against cardiovascular events. Here, we revealed a novel link between the rs599839 variant and hepatocellular carcinoma (HCC) whose onset in the context of NAFLD is rapidly increasing. We found that the rs599839 variant disentangled the risk of HCC from that of cardiovascular abnormalities by modulating SORT1 and PSRC1 expressions. The latter emerged as a potential modifier of liver carcinogenesis. Abstract Background and Aims: Dyslipidemia and cardiovascular diseases (CVD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 gene cluster, has been associated CVD, but its impact on metabolic traits and on the severity liver damage in NAFLD has not been investigated yet. Methods: We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 had HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC), and in 366 HCC samples from The Cancer Genome Atlas (TCGA). Hepatic PSRC1, SORT1 and CELSR2 expressions were evaluated by RNAseq (n = 125). Results: The rs599839 variant was associated with reduced circulating LDL, carotid intima-media thickness, carotid plaques and hypertension (p < 0.05) in NAFLD patients and with protection against dyslipidemia in UKBBC. The minor G allele was associated with higher risk of HCC, independently of fibrosis severity (odds ratio (OR): 5.62; 95% c.i. 1.77–17.84, p = 0.003), poor prognosis and advanced tumor stage (p < 0.05) in the overall cohort. Hepatic PSRC1, SORT1 and CELSR2 expressions were increased in NAFLD patients carrying the rs599839 variant (p < 0.0001). SORT1 mRNA levels negatively correlated with circulating lipids and with those of genes involved in lipoprotein turnover (p < 0.0001). Conversely, PSRC1 expression was positively related to that of genes implicated in cell proliferation (p < 0.0001). In TCGA, PSRC1 over-expression promoted more aggressive HCC development (p < 0.05). Conclusions: In sum, the rs599839 A>G variant is associated with protection against dyslipidemia and CVD in NAFLD patients, but as one it might promote HCC development by modulating SORT1 and PSRC1 expressions which impact on lipid metabolism and cell proliferation, respectively.
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20
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Li B, Veturi Y, Verma A, Bradford Y, Daar ES, Gulick RM, Riddler SA, Robbins GK, Lennox JL, Haas DW, Ritchie MD. Tissue specificity-aware TWAS (TSA-TWAS) framework identifies novel associations with metabolic, immunologic, and virologic traits in HIV-positive adults. PLoS Genet 2021; 17:e1009464. [PMID: 33901188 PMCID: PMC8102009 DOI: 10.1371/journal.pgen.1009464] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 05/06/2021] [Accepted: 03/03/2021] [Indexed: 01/01/2023] Open
Abstract
As a type of relatively new methodology, the transcriptome-wide association study (TWAS) has gained interest due to capacity for gene-level association testing. However, the development of TWAS has outpaced statistical evaluation of TWAS gene prioritization performance. Current TWAS methods vary in underlying biological assumptions about tissue specificity of transcriptional regulatory mechanisms. In a previous study from our group, this may have affected whether TWAS methods better identified associations in single tissues versus multiple tissues. We therefore designed simulation analyses to examine how the interplay between particular TWAS methods and tissue specificity of gene expression affects power and type I error rates for gene prioritization. We found that cross-tissue identification of expression quantitative trait loci (eQTLs) improved TWAS power. Single-tissue TWAS (i.e., PrediXcan) had robust power to identify genes expressed in single tissues, but, often found significant associations in the wrong tissues as well (therefore had high false positive rates). Cross-tissue TWAS (i.e., UTMOST) had overall equal or greater power and controlled type I error rates for genes expressed in multiple tissues. Based on these simulation results, we applied a tissue specificity-aware TWAS (TSA-TWAS) analytic framework to look for gene-based associations with pre-treatment laboratory values from AIDS Clinical Trial Group (ACTG) studies. We replicated several proof-of-concept transcriptionally regulated gene-trait associations, including UGT1A1 (encoding bilirubin uridine diphosphate glucuronosyltransferase enzyme) and total bilirubin levels (p = 3.59×10-12), and CETP (cholesteryl ester transfer protein) with high-density lipoprotein cholesterol (p = 4.49×10-12). We also identified several novel genes associated with metabolic and virologic traits, as well as pleiotropic genes that linked plasma viral load, absolute basophil count, and/or triglyceride levels. By highlighting the advantages of different TWAS methods, our simulation study promotes a tissue specificity-aware TWAS analytic framework that revealed novel aspects of HIV-related traits.
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Affiliation(s)
- Binglan Li
- Department of Biomedical Data Science, Stanford University, Stanford, California, United States of America
| | - Yogasudha Veturi
- Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Anurag Verma
- Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Yuki Bradford
- Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Eric S. Daar
- Lundquist Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America
| | - Roy M. Gulick
- Weill Cornell Medicine, New York City, New York, United States of America
| | - Sharon A. Riddler
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Gregory K. Robbins
- Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Jeffrey L. Lennox
- Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - David W. Haas
- Departments of Medicine, Pharmacology, Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee, United States of America
| | - Marylyn D. Ritchie
- Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
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21
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Al-Eitan LN, Elsaqa BZ, Almasri AY, Aman HA, Khasawneh RH, Alghamdi MA. Influence of PSRC1, CELSR2, and SORT1 Gene Polymorphisms on the Variability of Warfarin Dosage and Susceptibility to Cardiovascular Disease. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2020; 13:619-632. [PMID: 33235484 PMCID: PMC7680183 DOI: 10.2147/pgpm.s274246] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/15/2020] [Indexed: 12/27/2022]
Abstract
Background Cardiovascular disease is one of the most common causes of morbidity and mortality worldwide. Several cardiovascular diseases require therapy with warfarin, an anticoagulant with large interindividual variability resulting in dosing difficulties. The selected genes and their polymorphisms have been implicated in several Genome-Wide Association Study (GWAS) to be associated with cardiovascular disease. Objective The goal of this study is to discover if there are any associations between rs646776 of PSRC1, rs660240 and rs12740374 of CELSR2, and rs602633 of SORT1 to coronary heart disease (CHD) and warfarin dose variability in patients diagnosed with cardiovascular disease undergoing warfarin therapy. Methods The study was directed at the Queen Alia Hospital Anticoagulation Clinic in Amman, Jordan. DNA was extracted and genotyped using the Mass ARRAY™ system, statistical analysis was done using SPSS. Results The study found several associations between the selected SNPs with warfarin, but none with cardiovascular disease. All 4 studied SNPs were found to be correlated to warfarin sensitivity during the stabilization phase except rs602633 and with warfarin dose variability at the initiation phase. CELSR2 SNPs also showed association with dose variability during the stabilization phase. Also, rs646776 and rs12740374 were linked to warfarin sensitivity over the initiation phase. Only rs602633 was associated with INR treatment outcomes. Conclusion The findings presented in this study found new pharmacogenomic associations for warfarin, that warrant further research in the field of genotype-guided warfarin dosing.
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Affiliation(s)
- Laith N Al-Eitan
- Department of Biotechnology and Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Barakat Z Elsaqa
- Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Ayah Y Almasri
- Department of Biotechnology and Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Hatem A Aman
- Department of Biotechnology and Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Rame H Khasawneh
- Department of Hematopathology, King Hussein Medical Center (KHMC), Royal Medical Services (RMS), Amman 11118, Jordan
| | - Mansour A Alghamdi
- Department of Anatomy, College of Medicine, King Khalid University, Abha 61421, Saudi Arabi.,Genomics and Personalized Medicine Unit, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia
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22
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Association of the PSRC1 rs599839 Variant with Coronary Artery Disease in a Mexican Population. ACTA ACUST UNITED AC 2020; 56:medicina56090427. [PMID: 32858814 PMCID: PMC7559377 DOI: 10.3390/medicina56090427] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 07/29/2020] [Accepted: 08/12/2020] [Indexed: 12/14/2022]
Abstract
Background and Objectives: Coronary artery disease (CAD) is a major health problem in México. The identification of modifiable risk factors and genetic biomarkers is crucial for an integrative and personalized CAD risk evaluation. In this work, we aimed to validate in a Mexican population a set of eight selected polymorphisms previously associated with CAD, myocardial infarction (MI), or dyslipidemia. Materials and Methods: A sample of 907 subjects (394 CAD cases and 513 controls) 40–80 years old was genotyped for eight loci: PSRC1 (rs599839), MRAS (rs9818870), BTN2A1 (rs6929846), MTHFD1L (rs6922269), CDKN2B (rs1333049), KIAA1462 (rs3739998), CXCL12 (rs501120), and HNF1A (rs2259816). The association between single nucleotide polymorphisms (SNPs) and CAD was evaluated by logistic regression models. Results: Multiple logistic regression analysis with adjustment by age, gender, and body mass index showed that rs599839 was significantly associated with CAD (ORADD = 0.72, p = 0.009; ORDOM = 0.66, p = 0.007). Conclusions: The PSRC1 rs599839 polymorphism shows a significant protective association with CAD in this sample of the Mexican population.
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23
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Ouyang S, Jia B, Xie W, Yang J, Lv Y. Mechanism underlying the regulation of sortilin expression and its trafficking function. J Cell Physiol 2020; 235:8958-8971. [PMID: 32474917 DOI: 10.1002/jcp.29818] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 05/08/2020] [Accepted: 05/12/2020] [Indexed: 12/16/2022]
Abstract
This review summarizes and analyzes the updated information on the regulation of sortilin expression and its trafficking function. Evidence indicates that the expression and function of sortilin are closely regulated at four levels: DNA, messenger RNA (mRNA), protein, and trafficking function. DNA methylation, several mutations, and minor single-nucleotide polymorphisms within DNA fragments affect the expression of SORT1 gene. A few transcription factors and microRNAs modulate its transcription as well as the splicing or stability of the mRNA. Moreover, several translation factors control the synthesis of sortilin protein, and posttranslational modifications affect its degradation processes. Multiple adaptor molecules modulate the sortilin trafficking function in the anterograde or retrograde pathway. Recent advances in the regulation of sortilin expression and function, and its related mechanisms will help the ongoing research related to sortilin and promote future clinical application via sortilin intervention.
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Affiliation(s)
- Shuhui Ouyang
- Department of Anatomy, Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical College, University of South China, Hengyang, China
| | - Bo Jia
- Department of Anatomy, Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical College, University of South China, Hengyang, China
| | - Wei Xie
- Department of Anatomy, Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical College, University of South China, Hengyang, China
| | - Jing Yang
- Department of Endocrinology of the First Affiliated Hospital, Hengyang Medical College, University of South China, Hengyang, China
| | - Yuncheng Lv
- Department of Anatomy, Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical College, University of South China, Hengyang, China.,Guangxi Key Laboratory of Diabetic Systems Medicine, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin, China
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24
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The impact of PSRC1 overexpression on gene and transcript expression profiling in the livers of ApoE -/- mice fed a high-fat diet. Mol Cell Biochem 2019; 465:125-139. [PMID: 31838625 DOI: 10.1007/s11010-019-03673-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 12/03/2019] [Indexed: 01/16/2023]
Abstract
Our previous studies have confirmed that proline/serine-rich coiled-coil 1 (PSRC1) overexpression can regulate blood lipid levels and inhibit atherosclerosis (AS) development. In the current study, the gene and transcript expression profiles in the livers of ApoE-/- mice overexpressing PSRC1 were investigated. HiSeq X Ten RNA sequencing (RNA-seq) analysis was used to examine the differentially expressed genes (DEGs) and differentially expressed transcripts in the livers of PSRC1-overexpressing ApoE-/- and control mice. Then, Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on these DEGs and on long noncoding RNA (lncRNA) predicted target genes. A total of 1892 significant DEGs were identified: 1431 were upregulated (e.g., Cyp2a4, Obp2a, and Sertad4), and 461 were downregulated (e.g., Moxd1, Egr1, and Elovl3). In addition, 8184 significant differentially expressed transcripts were identified, 4908 of which were upregulated and 3276 of which were downregulated. Furthermore, 1106 significant differentially expressed lncRNAs were detected, 713 of which were upregulated and 393 of which were downregulated. Quantitative reverse transcription PCR (qRT-PCR) verified changes in 10 randomly selected DEGs. GO analyses showed that the DEGs and predicted lncRNA target genes were mostly enriched for actin binding and lipid metabolism. KEGG biological pathway analyses showed that the DEGs in the livers of PSRC1-overexpressing ApoE-/- mice were enriched in the mitogen-activated protein kinase (MAPK) pathway. These findings reveal that PSRC1 may affect liver actin polymerization and cholesterol metabolism-related genes or pathways. These mRNAs and lncRNAs may represent new biomarkers and targets for the diagnosis and therapy of lipid metabolism disturbance and AS.
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25
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Andaleon A, Mogil LS, Wheeler HE. Genetically regulated gene expression underlies lipid traits in Hispanic cohorts. PLoS One 2019; 14:e0220827. [PMID: 31393916 PMCID: PMC6687110 DOI: 10.1371/journal.pone.0220827] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 07/23/2019] [Indexed: 01/17/2023] Open
Abstract
Plasma lipid levels are risk factors for cardiovascular disease, a leading cause of death worldwide. While many studies have been conducted in genetic variation underlying lipid levels, they mainly comprise individuals of European ancestry and thus their transferability to non-European populations is unclear. We performed genome-wide (GWAS) and imputed transcriptome-wide association studies of four lipid traits in the Hispanic Community Health Study/Study of Latinos cohort (HCHS/SoL, n = 11,103), replicated top hits in the Multi-Ethnic Study of Atherosclerosis (MESA, n = 3,855), and compared the results to the larger, predominantly European ancestry meta-analysis by the Global Lipids Genetics Consortium (GLGC, n = 196,475). In our GWAS, we found significant SNP associations in regions within or near known lipid genes, but in our admixture mapping analysis, we did not find significant associations between local ancestry and lipid phenotypes. In the imputed transcriptome-wide association study in multiple tissues and in different ethnicities, we found 59 significant gene-tissue-phenotype associations (P < 3.61×10-8) with 14 unique significant genes, many of which occurred across multiple phenotypes, tissues, and ethnicities and replicated in MESA (45/59) and in GLGC (44/59). These include well-studied lipid genes such as SORT1, CETP, and PSRC1, as well as genes that have been implicated in cardiovascular phenotypes, such as CCL22 and ICAM1. The majority (40/59) of significant associations colocalized with expression quantitative trait loci (eQTLs), indicating a possible mechanism of gene regulation in lipid level variation. To fully characterize the genetic architecture of lipid traits in diverse populations, larger studies in non-European ancestry populations are needed.
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Affiliation(s)
- Angela Andaleon
- Department of Biology, Loyola University Chicago, Chicago, IL, United States of America
- Program in Bioinformatics, Loyola University Chicago, Chicago, IL, United States of America
| | - Lauren S. Mogil
- Department of Biology, Loyola University Chicago, Chicago, IL, United States of America
| | - Heather E. Wheeler
- Department of Biology, Loyola University Chicago, Chicago, IL, United States of America
- Program in Bioinformatics, Loyola University Chicago, Chicago, IL, United States of America
- Department of Computer Science, Loyola University Chicago, Chicago, IL, United States of America
- Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, United States of America
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26
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Kovac U, Jasper EA, Smith CJ, Baer RJ, Bedell B, Donovan BM, Weathers N, Prosenc Zmrzljak U, Jelliffe-Pawlowski LL, Rozman D, Ryckman KK. The Association of Polymorphisms in Circadian Clock and Lipid Metabolism Genes With 2 nd Trimester Lipid Levels and Preterm Birth. Front Genet 2019; 10:540. [PMID: 31249592 PMCID: PMC6584752 DOI: 10.3389/fgene.2019.00540] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 05/17/2019] [Indexed: 12/19/2022] Open
Abstract
Deregulation of the circadian system in humans and animals can lead to various adverse reproductive outcomes due to genetic mutations and environmental factors. In addition to the clock, lipid metabolism may also play an important role in influencing reproductive outcomes. Despite the importance of the circadian clock and lipid metabolism in regulating birth timing few studies have examined the relationship between circadian genetics with lipid levels during pregnancy and their relationship with preterm birth (PTB). In this study we aimed to determine if single nucleotide polymorphisms (SNPs) in genes from the circadian clock and lipid metabolism influence 2nd trimester maternal lipid levels and if this is associated with an increased risk for PTB. We genotyped 72 SNPs across 40 genes previously associated with various metabolic abnormalities on 930 women with 2nd trimester serum lipid measurements. SNPs were analyzed for their relationship to levels of total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglycerides (TG) using linear regression. SNPs were also evaluated for their relationship to PTB using logistic regression. Five SNPs in four genes met statistical significance after Bonferroni correction (p < 1.8 × 10-4) with one or more lipid levels. Of these, four SNPs were in lipid related metabolism genes: rs7412 in APOE with total cholesterol, HDL and LDL, rs646776 and rs599839 in CELSR2-PSRC1-SORT1 gene cluster with total cholesterol, HDL and LDL and rs738409 in PNPLA3 with HDL and TG and one was in a circadian clock gene: rs228669 in PER3 with TG. Of these SNPs only PER3 rs228669 was marginally associated with PTB (p = 0.02). In addition, PER3 rs228669 acts as an effect modifier on the relationship between TG and PTB.
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Affiliation(s)
- Ursa Kovac
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Elizabeth A Jasper
- Department of Epidemiology, The University of Iowa, Iowa City, IA, United States
| | - Caitlin J Smith
- Department of Epidemiology, The University of Iowa, Iowa City, IA, United States
| | - Rebecca J Baer
- Department of Pediatrics, University of California, San Diego, San Diego, CA, United States.,California Preterm Birth Initiative, University of California, San Francisco, San Francisco, CA, United States
| | - Bruce Bedell
- Department of Epidemiology, The University of Iowa, Iowa City, IA, United States
| | - Brittney M Donovan
- Department of Epidemiology, The University of Iowa, Iowa City, IA, United States
| | - Nancy Weathers
- Department of Epidemiology, The University of Iowa, Iowa City, IA, United States
| | - Ursula Prosenc Zmrzljak
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Laura L Jelliffe-Pawlowski
- California Preterm Birth Initiative, University of California, San Francisco, San Francisco, CA, United States.,Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States
| | - Damjana Rozman
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Kelli K Ryckman
- Department of Epidemiology, The University of Iowa, Iowa City, IA, United States
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Bandesh K, Prasad G, Giri AK, Kauser Y, Upadhyay M, Basu A, Tandon N, Bharadwaj D. Genome-wide association study of blood lipids in Indians confirms universality of established variants. J Hum Genet 2019; 64:573-587. [PMID: 30911093 DOI: 10.1038/s10038-019-0591-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 03/02/2019] [Accepted: 03/03/2019] [Indexed: 12/30/2022]
Abstract
Lipids foster energy production and their altered levels have been coupled with metabolic ailments. Indians feature high prevalence of metabolic diseases, yet uncharacterized for genes regulating lipid homeostasis. We performed first GWAS for quantitative lipids (total cholesterol, LDL, HDL, and triglycerides) exclusively in 5271 Indians. Further to corroborate our genetic findings, we investigated DNA methylation marks in peripheral blood in Indians at the identified loci (N = 233) and retrieved gene regulatory features from public domains. Recurrent GWAS loci-CELSR2, CETP, LPL, ZNF259, and BUD13 cropped up as lead signals in Indians, reflecting their universal applicability. Besides established variants, we found certain unreported variants at sub-genome-wide level-QKI, REEP3, TMCC2, FAM129C, FAM241B, and LOC100506207. These variants though failed to attain GWAS significance in Indians, but largely turned out to be active CpG sites in human subcutaneous adipose tissue and showed robust association to two or more lipid traits. Of which, QKI variants showed significant association to all four lipid traits and their designated region was observed to be a key gene regulatory segment denoting active transcription particularly in human subcutaneous adipose tissue. Both established and novel loci were observed to be significantly associated with altered DNA methylation in Indians for specific CpGs that resided in key regulatory elements. Further, gene-based association analysis pinpointed novel GWAS loci-LINC01340 and IQCJ-SCHIP1 for TC; IFT27, IFT88, and LINC02141 for HDL; and TEX26 for TG. Present study ascertains universality of selected known genes and also identifies certain novel loci for lipids in Indians by integrating data from various levels of gene regulation.
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Affiliation(s)
- Khushdeep Bandesh
- Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, 110020, India.,Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, 110020, India
| | - Gauri Prasad
- Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, 110020, India.,Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, 110020, India
| | - Anil K Giri
- Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, 110020, India.,Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, 110020, India
| | - Yasmeen Kauser
- Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, 110020, India.,Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, 110020, India
| | - Medha Upadhyay
- Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India
| | | | - Analabha Basu
- National Institute of Biomedical Genomics, P.O.: Netaji Subhas Sanatorium, Kalyani, 741251, West Bengal, India
| | - Nikhil Tandon
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Dwaipayan Bharadwaj
- Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, 110020, India. .,Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India.
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There is an association between a genetic polymorphism in the ZNF259 gene involved in lipid metabolism and coronary artery disease. Gene 2019; 704:80-85. [PMID: 30902787 DOI: 10.1016/j.gene.2019.02.101] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 02/09/2019] [Accepted: 02/22/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Recent genome-wide association studies (GWAS) have identified several genetic variants that influence the risk of dyslipidemia and coronary artery disease (CAD). In this study, we have examined the potential association of five SNPs variants related to lipid pathway, previously identified in GWAS studies (ZNF259 C>G, CETP I405VA/G, LPA C>T, LPLS447X and PSRC1 A>G) with CAD. METHODS Two hundred and ninety subjects including 194 patients with coronary artery disease and 96 controls were enrolled, followed by the analyses of anthropometric/biochemical parameters. Genotyping was carried out using Taq-Man real-time PCR based method. The association of the genetic polymorphisms with CAD was determined using univariate and multivariate analyses. RESULTS CAD patients had a higher (p < 0.05) fasting blood glucose (FBG), total cholesterol (TC), high sensitivity C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C) and waist circumference. Results showed that subjects with CETP rs5882 genetic variant, AA&AG genotypes, had a higher risk of developing Coronary artery disease [OR: 2.1, 95% CI (1.2-4.1), p value = 0.015]. Also subjects who carried the G allele of the ZNF259 polymorphism were at an increased the risk of developing CAD [OR 1.86, 95% CI: 1.06-3.25, p value = 0.029] and had an increased TC, LDL and TG levels (p < 0.05). Furthermore, no statistically significant association was found between genetic polymorphisms of PSRC1 A>G, LPL S447X and LPA C>T and CAD. CONCLUSION We identified a relationship between a genetic variant in CETP and ZNF259 gene with CAD and CAD and lipid profile, respectively. Further investigation in a larger population may help to investigate the value of emerging marker as a risk stratification marker in CAD and its risk factors.
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Taylor K, Davey Smith G, Relton CL, Gaunt TR, Richardson TG. Prioritizing putative influential genes in cardiovascular disease susceptibility by applying tissue-specific Mendelian randomization. Genome Med 2019; 11:6. [PMID: 30704512 PMCID: PMC6354354 DOI: 10.1186/s13073-019-0613-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 01/08/2019] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The extent to which changes in gene expression can influence cardiovascular disease risk across different tissue types has not yet been systematically explored. We have developed an analysis pipeline that integrates tissue-specific gene expression, Mendelian randomization and multiple-trait colocalization to develop functional mechanistic insight into the causal pathway from a genetic variant to a complex trait. METHODS We undertook an expression quantitative trait loci-wide association study to uncover genetic variants associated with both nearby gene expression and cardiovascular traits. Fine-mapping was performed to prioritize possible causal variants for detected associations. Two-sample Mendelian randomization (MR) was then applied using findings from genome-wide association studies (GWAS) to investigate whether changes in gene expression within certain tissue types may influence cardiovascular trait variation. We subsequently used Bayesian multiple-trait colocalization to further interrogate the findings and also gain insight into whether DNA methylation, as well as gene expression, may play a role in disease susceptibility. Finally, we applied our analysis pipeline genome-wide using summary statistics from large-scale GWAS. RESULTS Eight genetic loci were associated with changes in gene expression and measures of cardiovascular function. Our MR analysis provided evidence of tissue-specific effects at multiple loci, of which the effects at the ADCY3 and FADS1 loci for body mass index and cholesterol, respectively, were particularly insightful. Multiple-trait colocalization uncovered evidence which suggested that changes in DNA methylation at the promoter region upstream of FADS1/TMEM258 may also affect cardiovascular trait variation along with gene expression. Furthermore, colocalization analyses uncovered evidence of tissue specificity between gene expression in liver tissue and cholesterol levels. Applying our pipeline genome-wide using summary statistics from GWAS uncovered 233 association signals at loci which represent promising candidates for further evaluation. CONCLUSIONS Disease susceptibility can be influenced by differential changes in tissue-specific gene expression and DNA methylation. The approach undertaken in our study can be used to elucidate mechanisms in disease, as well as helping prioritize putative causal genes at associated loci where multiple nearby genes may be co-regulated. Future studies which continue to uncover quantitative trait loci for molecular traits across various tissue and cell types will further improve our capability to understand and prevent disease.
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Affiliation(s)
- Kurt Taylor
- MRC Integrative Epidemiology Unit, Bristol Medical School (Population Health Sciences), University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
| | - George Davey Smith
- MRC Integrative Epidemiology Unit, Bristol Medical School (Population Health Sciences), University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
- National Institute for Health Research Biomedical Research Centre, Bristol, UK
| | - Caroline L Relton
- MRC Integrative Epidemiology Unit, Bristol Medical School (Population Health Sciences), University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
- National Institute for Health Research Biomedical Research Centre, Bristol, UK
| | - Tom R Gaunt
- MRC Integrative Epidemiology Unit, Bristol Medical School (Population Health Sciences), University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
- National Institute for Health Research Biomedical Research Centre, Bristol, UK
| | - Tom G Richardson
- MRC Integrative Epidemiology Unit, Bristol Medical School (Population Health Sciences), University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
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Qin J, Tian J, Liu G, Zhang Y, Tian L, Zhen Y, Zhang H, Xu J, Sun X, Fang H. Association between 1p13 polymorphisms and peripheral arterial disease in a Chinese population with diabetes. J Diabetes Investig 2018; 9:1189-1195. [PMID: 29356453 PMCID: PMC6123029 DOI: 10.1111/jdi.12804] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 01/09/2018] [Accepted: 01/10/2018] [Indexed: 01/06/2023] Open
Abstract
AIMS/INTRODUCTION Variants on chromosome 1p13 have been associated with coronary artery disease and acute myocardial infarction risk in different ethnic groups. The present study aimed to investigate the association between 1p13 polymorphisms and the development of peripheral artery disease (PAD) in a Chinese population with type 2 diabetes mellitus. MATERIALS AND METHODS 1p13 polymorphisms, rs599839, rs646776 and rs12740374, were assessed in a cohort of 882 type 2 diabetes mellitus patients including 440 type 2 diabetes mellitus patients with PAD (DM + PAD group) and 442 patients without PAD (DM group). Genotyping was carried out using TaqMan assay. RESULTS Compared with the DM group, the frequencies of the minor G allele of both rs599839 and rs646776 and the minor T allele of rs12740374 decreased (P = 0.013, P = 0.019 and P = 0.005, respectively), and the frequencies of rs599839 AG + GG, rs646776 AG + GG and rs12740374 CT+TT genotypes were statistically significantly decreased as well (P = 0.017, P = 0.011 and P = 0.007, respectively) in the dominant model in the DM + PAD group than in the DM group. Multivariate unconditional logistic regression analyses adjusted for age, glycated hemoglobin, triglyceride, low-density lipoprotein cholesterol, smoking, hypertension, diabetes duration, coronary heart disease and cerebral infarction showed that the genotypic distribution of rs599839 AG + GG, rs646776 AG + GG and rs12740374 CT + TT remained statistically different between the DM and DM + PAD group (P = 0.014, P = 0.003 and P = 0.004, respectively). The frequencies of haplotype GGT were statistically significantly different between groups (P = 0.08). CONCLUSIONS The present study strongly supports that genotypes of rs599839, rs646776 and rs12740374 on 1p13 are protective factors for diabetic PAD in a Chinese population. Haplotype GGT generated by rs599839, rs646776 and rs12740374 might also decrease the risk of the disease.
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Affiliation(s)
- Jiangyuan Qin
- Department of Internal MedicineHebei Medical UniversityShijiazhuangHebeiChina
| | - Jinli Tian
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Guanhua Liu
- Department of OrthopedicsTangshan Gongren HospitalTangshanHebeiChina
| | - Yazhong Zhang
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Luobing Tian
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Yanfeng Zhen
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Hewei Zhang
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Jing Xu
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Xueling Sun
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Hui Fang
- Department of Internal MedicineHebei Medical UniversityShijiazhuangHebeiChina
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
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Xi D, Zhao J, Guo K, Hu L, Chen H, Fu W, Lai W, Guo Z. Serum amyloid P component therapeutically attenuates atherosclerosis in mice via its effects on macrophages. Am J Cancer Res 2018; 8:3214-3223. [PMID: 29930724 PMCID: PMC6010983 DOI: 10.7150/thno.22704] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 03/09/2018] [Indexed: 11/15/2022] Open
Abstract
Background: A hallmark of atherosclerosis is the formation of macrophage-derived foam cells. Serum amyloid P component (SAP), a member of the pentraxin family of proteins, is known to affect macrophage activation. However, the role of SAP in atherosclerosis is still unclear. Methods: Apolipoprotein E-deficient (Apoe-/-) mice fed a high-fat diet were given intraperitoneal injections of SAP (6 mg/kg) every other day for a total of 2 weeks to characterize atherosclerosis development. Results: We showed that intraperitoneal injection of SAP attenuated atherosclerosis in Apoe-/- mice. Immunostaining of aortic roots indicated that SAP was up-taken by the lesion area. In SAP-treated mice, serum paraoxonase1 (PON1) activity was increased whereas high-density lipoprotein inflammatory index (HII) was reduced. The cholesterol efflux rate in macrophages was elevated along with the expression of cholesterol efflux proteins. Through bioinformatics analysis followed by experimental validation, we found that proline/serine-rich coiled-coil protein 1 (Psrc1) was an important downstream effector of SAP in macrophages. Conclusions: Our findings reveal an anti-atherosclerotic role of SAP and extend the current knowledge regarding this molecule as a marker for atherosclerosis.
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Emam RH, Ghattas MH, Mesbah NM, Abo-Elmatty DM, Mehanna ET. Relation of locus 1p13 rs646776 polymorphism with the risk of preeclampsia. Hypertens Pregnancy 2018; 37:81-86. [PMID: 29575956 DOI: 10.1080/10641955.2018.1454462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
OBJECTIVE This study aimed to assess the relation of locus 1p13 rs646776 (T/C) polymorphism with preeclampsia in Egyptian women. METHODS The study included 100 healthy pregnant female subjects and 100 preeclampsia patients. The genotypes of the polymorphisms were assessed. Endothelin-1 level was determined in plasma. RESULTS The major T allele of the 1p13.3 genomic region rs646776 polymorphism had a higher frequency in preeclampsia patients. Carriers of C allele had significantly lower endothelin-1 levels, lower systolic and diastolic blood pressure, decreased proteinuria, and increased HDL-C in the patients. CONCLUSION The rare C allele of rs646776 polymorphism in chromosomal locus 1p13.3 is associated with decreased risk of preeclampsia.
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Affiliation(s)
- Rana H Emam
- a Faculty of Pharmacy, Department of Biochmistry , Suez Canal University , Ismailia , Egypt
| | - Maivel H Ghattas
- b Faculty of Medicine, Department of Medical Biochemistry , Port Said University , Port Said , Egypt
| | - Noha M Mesbah
- a Faculty of Pharmacy, Department of Biochmistry , Suez Canal University , Ismailia , Egypt
| | - Dina M Abo-Elmatty
- a Faculty of Pharmacy, Department of Biochmistry , Suez Canal University , Ismailia , Egypt
| | - Eman T Mehanna
- a Faculty of Pharmacy, Department of Biochmistry , Suez Canal University , Ismailia , Egypt
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Guo K, Hu L, Xi D, Zhao J, Liu J, Luo T, Ma Y, Lai W, Guo Z. PSRC1 overexpression attenuates atherosclerosis progression in apoE -/- mice by modulating cholesterol transportation and inflammation. J Mol Cell Cardiol 2018; 116:69-80. [PMID: 29378206 DOI: 10.1016/j.yjmcc.2018.01.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 01/16/2018] [Accepted: 01/20/2018] [Indexed: 01/13/2023]
Abstract
AIMS Human genome-wide association studies (GWAS) have found that proline/serine-rich coiled-coil 1 (PSRC1) encodes a protein that is associated with serum lipid levels and coronary artery disease. In addition, our previous study showed that the cholesterol efflux capacity is decreased in macrophages following a treatment silencing Psrc1, indicating that PSRC1 has anti-atherosclerotic effects. However, the role of PSRC1 in the development of atherosclerosis is unknown. This study aims to explore the effect of PSRC1 on atherosclerosis and its underlying mechanisms. METHOD AND RESULTS A recombinant adenovirus expressing Psrc1 (Ad-PSRC1) was constructed and transfected in RAW264.7 cells as well as injected intravenously into apoE-/- mice. The in vitro study showed that PSRC1 overexpression reduced the cellular cholesterol content, increased the cholesterol efflux capacity and inhibited foam cell formation by upregulating the expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and liver X receptor α (LXR-α), which are key cholesterol transportation-related proteins. Infecting apoE-/- mice with Ad-PSRC1 inhibited the development of atherosclerotic lesions and enhanced atherosclerotic plaque stability. Consistent with these results, PSRC1 overexpression in apoE-/- mice decreased the plasma levels of TC, TG, LDL-C, TNF-α, IL-1β and IL-6, increased the plasma HDL-C levels and improved HDL function. Similarly, the PPAR-γ and LXR-α expression levels were upregulated in the liver and in peritoneal macrophages of PSRC1-overexpressing apoE-/- mice. Finally, the liver and peritoneal macrophages of apoE-/- mice displayed elevated expression of β-catenin, which is a direct downstream gene of PSRC1 and an upstream gene of PPAR-γ and LXR-α, but decreased activity of nuclear transcription factor (NF-κB), which acts as a key gene in the regulation of inflammation. CONCLUSIONS PSRC1 protects against the development of atherosclerosis and enhances the stability of plaques by modulating cholesterol transportation and inflammation in macrophages and the liver of apoE-/- mice.
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Affiliation(s)
- Kai Guo
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Lu Hu
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Dan Xi
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Jinzhen Zhao
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Jichen Liu
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Tiantian Luo
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Yusheng Ma
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Wenyan Lai
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Zhigang Guo
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China.
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Andersson CH, Hansson O, Minthon L, Andreasen N, Blennow K, Zetterberg H, Skoog I, Wallin A, Nilsson S, Kettunen P. A Genetic Variant of the Sortilin 1 Gene is Associated with Reduced Risk of Alzheimer's Disease. J Alzheimers Dis 2018; 53:1353-63. [PMID: 27392867 PMCID: PMC5147507 DOI: 10.3233/jad-160319] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc = 0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD.
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Affiliation(s)
- Carl-Henrik Andersson
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Oskar Hansson
- Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Sweden.,Memory Clinic, Skåne University Hospital, Malmö, Sweden
| | - Lennart Minthon
- Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Sweden.,Memory Clinic, Skåne University Hospital, Malmö, Sweden
| | - Niels Andreasen
- Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden
| | - Kaj Blennow
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Henrik Zetterberg
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,UCL Institute of Neurology, Queen Square, London, United Kingdom
| | - Ingmar Skoog
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anders Wallin
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Staffan Nilsson
- Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Sweden
| | - Petronella Kettunen
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Neuropathology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
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Alharbi KK, Ali Khan I, Alotaibi MA, Saud Aloyaid A, Al-Basheer HA, Alghamdi NA, Al-Baradie RS, Al-Sulaiman A. Molecular genetic studies in Saudi population; identified variants from GWAS and meta-analysis in stroke. Saudi J Biol Sci 2018; 25:83-89. [PMID: 29379361 PMCID: PMC5775098 DOI: 10.1016/j.sjbs.2017.08.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 08/09/2017] [Accepted: 08/22/2017] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Stroke is a multifactorial and heterogeneous disorder, correlates with heritability and considered as one of the major diseases. The prior reports performed the variable models such as genome-wide association studies (GWAS), replication, case-control, cross-sectional and meta-analysis studies and still, we lack diagnostic marker in the global world. There are limited studies were carried out in Saudi population, and we aim to investigate the molecular association of single nucleotide polymorphisms (SNPs) identified through GWAS and meta-analysis studies in stroke patients in the Saudi population. METHODS In this case-control study, we have opted gender equality of 207 cases and 207 controls from the capital city of Saudi Arabia in King Saud University Hospital. The peripheral blood (5 ml) sample will be collected in two different vacutainers, and three mL of the coagulated blood will be used for lipid analysis (biochemical tests) and two mL will be used for DNA analysis (molecular tests). Genomic DNA will be extracted with the collected blood samples, and specific primers will be designed for the opted SNPs (SORT1-rs646218 and OLR1-rs11053646 polymorphisms) and PCR-RFLP will be performed and randomly DNA sequencing will be carried out to cross check the results. RESULTS The rs646218 and rs11053646 polymorphisms were significantly associated with allele, genotype and dominant models with and without crude odds ratios (OR's) and Multiple logistic regression analysis (p < 0.05). Correlation between lipid profile and genotypes has confirmed the significant relation between triglycerides and rs646218 and rs1105364 6polymorphisms. However, rs11053646 polymorphism was correlated with HDLC (p = 0.04). Genotypes were examined in both males' vs. males and females' vs. females in cases and control and we concluded that in rs11053646 polymorphisms with male subjects compared between cases and controls found to be associated with dominant model heterozygote genotypes (p < 0.05). CONCLUSION The results of the current study confirmed the SORT1 and OLR1 SNPs were associated in the Saudi population. The current results were in the association with the prior study results documented through GWAS and meta-analysis association. However, other ethnic population studies should be performed to rule out in the human hereditary diseases.
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Affiliation(s)
- Khalid Khalaf Alharbi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia
| | - Imran Ali Khan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia
| | | | | | | | - Naelah Abdullah Alghamdi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia
| | | | - A.M. Al-Sulaiman
- Department of Medical and Molecular Virology, PSMMC, Riyadh, Saudi Arabia
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Gao A, Cayabyab FS, Chen X, Yang J, Wang L, Peng T, Lv Y. Implications of Sortilin in Lipid Metabolism and Lipid Disorder Diseases. DNA Cell Biol 2017; 36:1050-1061. [DOI: 10.1089/dna.2017.3853] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Anbo Gao
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, China
| | - Francisco S. Cayabyab
- Department of Surgery, College of Medicine, University of Saskatchewan, Saskatoon, Canada
| | - Xi Chen
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, China
| | - Jing Yang
- Department of Metabolism & Endocrinology, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Li Wang
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, China
| | - Tianhong Peng
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, China
| | - Yuncheng Lv
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, China
- Department of Surgery, College of Medicine, University of Saskatchewan, Saskatoon, Canada
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Goettsch C, Kjolby M, Aikawa E. Sortilin and Its Multiple Roles in Cardiovascular and Metabolic Diseases. Arterioscler Thromb Vasc Biol 2017; 38:19-25. [PMID: 29191923 DOI: 10.1161/atvbaha.117.310292] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 11/16/2017] [Indexed: 12/24/2022]
Abstract
Cardiovascular disease is a leading cause of morbidity and mortality in the Western world. Studies of sortilin's influence on cardiovascular and metabolic diseases goes far beyond the genome-wide association studies that have revealed an association between cardiovascular diseases and the 1p13 locus that encodes sortilin. Emerging evidence suggests a significant role of sortilin in the pathogenesis of vascular and metabolic diseases; this includes type II diabetes mellitus via regulation of insulin resistance, atherosclerosis through arterial wall inflammation and calcification, and dysregulated lipoprotein metabolism. Sortilin is also known for its functional role in neurological disorders. It serves as a key receptor for cytokines, lipids, and enzymes and participates in pathological cargo loading to and trafficking of extracellular vesicles. This article provides a comprehensive review of sortilin's contributions to cardiovascular and metabolic diseases but focuses particularly on atherosclerosis. We summarize recent clinical findings that suggest that sortilin may be a cardiovascular risk biomarker and also discuss sortilin as a potential drug target.
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Affiliation(s)
- Claudia Goettsch
- From the Department of Internal Medicine I-Cardiology, RWTH Aachen University, Germany (C.G.); The Danish Research Institute of Translational Neuroscience, Nordic European Molecular Biology Laboratory Partnership for Molecular Medicine, Danish Diabetes Academy, Denmark (M.K.); Department of Biomedicine (M.K.) and Department of Cardiology (M.K.), Aarhus University, Denmark; and Center for Interdisciplinary Cardiovascular Sciences (E.A.) and Center for Excellence in Vascular Biology, Division of Cardiovascular Medicine (E.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Mads Kjolby
- From the Department of Internal Medicine I-Cardiology, RWTH Aachen University, Germany (C.G.); The Danish Research Institute of Translational Neuroscience, Nordic European Molecular Biology Laboratory Partnership for Molecular Medicine, Danish Diabetes Academy, Denmark (M.K.); Department of Biomedicine (M.K.) and Department of Cardiology (M.K.), Aarhus University, Denmark; and Center for Interdisciplinary Cardiovascular Sciences (E.A.) and Center for Excellence in Vascular Biology, Division of Cardiovascular Medicine (E.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Elena Aikawa
- From the Department of Internal Medicine I-Cardiology, RWTH Aachen University, Germany (C.G.); The Danish Research Institute of Translational Neuroscience, Nordic European Molecular Biology Laboratory Partnership for Molecular Medicine, Danish Diabetes Academy, Denmark (M.K.); Department of Biomedicine (M.K.) and Department of Cardiology (M.K.), Aarhus University, Denmark; and Center for Interdisciplinary Cardiovascular Sciences (E.A.) and Center for Excellence in Vascular Biology, Division of Cardiovascular Medicine (E.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
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Trafficking in Alzheimer's Disease: Modulation of APP Transport and Processing by the Transmembrane Proteins LRP1, SorLA, SorCS1c, Sortilin, and Calsyntenin. Mol Neurobiol 2017; 55:5809-5829. [PMID: 29079999 DOI: 10.1007/s12035-017-0806-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 10/17/2017] [Indexed: 12/11/2022]
Abstract
The amyloid precursor protein (APP), one key player in Alzheimer's disease (AD), is extensively processed by different proteases. This leads to the generation of diverging fragments including the amyloid β (Aβ) peptide, which accumulates in brains of AD patients. Subcellular trafficking of APP is an important aspect for its proteolytic conversion, since the various secretases which cleave APP are located in different cellular compartments. As a consequence, altered subcellular targeting of APP is thought to directly affect the degree to which Aβ is generated. The mechanisms underlying intracellular APP transport are critical to understand AD pathogenesis and can serve as a target for future pharmacological interventions. In the recent years, a number of APP interacting proteins were identified which are implicated in sorting of APP, thereby influencing APP processing at different angles of the secretory or endocytic pathway. This review provides an update on the proteolytic processing of APP and the interplay of the transmembrane proteins low-density lipoprotein receptor-related protein 1, sortilin-receptor with A-type repeats, SorCS1c, sortilin, and calsyntenin. We discuss the specific interactions with APP, the capacity to modulate the intracellular itinerary and the proteolytic conversion of APP, a possible involvement in the clearance of Aβ, and the implications of these transmembrane proteins in AD and other neurodegenerative diseases.
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Paththinige CS, Sirisena ND, Dissanayake V. Genetic determinants of inherited susceptibility to hypercholesterolemia - a comprehensive literature review. Lipids Health Dis 2017; 16:103. [PMID: 28577571 PMCID: PMC5457620 DOI: 10.1186/s12944-017-0488-4] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 05/17/2017] [Indexed: 02/08/2023] Open
Abstract
Hypercholesterolemia is a strong determinant of mortality and morbidity associated with cardiovascular diseases and a major contributor to the global disease burden. Mutations in four genes (LDLR, APOB, PCSK9 and LDLRAP1) account for the majority of cases with familial hypercholesterolemia. However, a substantial proportion of adults with hypercholesterolemia do not have a mutation in any of these four genes. This indicates the probability of having other genes with a causative or contributory role in the pathogenesis of hypercholesterolemia and suggests a polygenic inheritance of this condition. Here in, we review the recent evidence of association of the genetic variants with hypercholesterolemia and the three lipid traits; total cholesterol (TC), HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C), their biological pathways and the associated pathogenetic mechanisms. Nearly 80 genes involved in lipid metabolism (encoding structural components of lipoproteins, lipoprotein receptors and related proteins, enzymes, lipid transporters, lipid transfer proteins, and activators or inhibitors of protein function and gene transcription) with single nucleotide variants (SNVs) that are recognized to be associated with hypercholesterolemia and serum lipid traits in genome-wide association studies and candidate gene studies were identified. In addition, genome-wide association studies in different populations have identified SNVs associated with TC, HDL-C and LDL-C in nearly 120 genes within or in the vicinity of the genes that are not known to be involved in lipid metabolism. Over 90% of the SNVs in both these groups are located outside the coding regions of the genes. These findings indicates that there might be a considerable number of unrecognized processes and mechanisms of lipid homeostasis, which when disrupted, would lead to hypercholesterolemia. Knowledge of these molecular pathways will enable the discovery of novel treatment and preventive methods as well as identify the biochemical and molecular markers for the risk prediction and early detection of this common, yet potentially debilitating condition.
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Affiliation(s)
- C S Paththinige
- Human Genetics Unit, Faculty of Medicine, University of Colombo, Kynsey Road, Colombo, 00800, Sri Lanka.
| | - N D Sirisena
- Human Genetics Unit, Faculty of Medicine, University of Colombo, Kynsey Road, Colombo, 00800, Sri Lanka
| | - Vhw Dissanayake
- Human Genetics Unit, Faculty of Medicine, University of Colombo, Kynsey Road, Colombo, 00800, Sri Lanka
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Marvel SW, Rotroff DM, Wagner MJ, Buse JB, Havener TM, McLeod HL, Motsinger-Reif AA. Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial. PeerJ 2017; 5:e3187. [PMID: 28480134 PMCID: PMC5417062 DOI: 10.7717/peerj.3187] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 03/15/2017] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Individuals with type 2 diabetes are at an increased risk of cardiovascular disease. Alterations in circulating lipid levels, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) are heritable risk factors for cardiovascular disease. Here we conduct a genome-wide association study (GWAS) of common and rare variants to investigate associations with baseline lipid levels in 7,844 individuals with type 2 diabetes from the ACCORD clinical trial. METHODS DNA extracted from stored blood samples from ACCORD participants were genotyped using the Affymetrix Axiom Biobank 1 Genotyping Array. After quality control and genotype imputation, association of common genetic variants (CV), defined as minor allele frequency (MAF) ≥ 3%, with baseline levels of TC, LDL, HDL, and TG was tested using a linear model. Rare variant (RV) associations (MAF < 3%) were conducted using a suite of methods that collapse multiple RV within individual genes. RESULTS Many statistically significant CV (p < 1 × 10-8) replicate findings in large meta-analyses in non-diabetic subjects. RV analyses also confirmed findings in other studies, whereas significant RV associations with CNOT2, HPN-AS1, and SIRPD appear to be novel (q < 0.1). DISCUSSION Here we present findings for the largest GWAS of lipid levels in people with type 2 diabetes to date. We identified 17 statistically significant (p < 1 × 10-8) associations of CV with lipid levels in 11 genes or chromosomal regions, all of which were previously identified in meta-analyses of mostly non-diabetic cohorts. We also identified 13 associations in 11 genes based on RV, several of which represent novel findings.
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Affiliation(s)
- Skylar W Marvel
- Bioinformatics Research Center, North Carolina State University, Raleigh, NC, United States of America
| | - Daniel M Rotroff
- Bioinformatics Research Center, North Carolina State University, Raleigh, NC, United States of America.,Department of Statistics, North Carolina State University, Raleigh, NC, United States of America
| | - Michael J Wagner
- Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America
| | - John B Buse
- Division of Endocrinology, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America
| | - Tammy M Havener
- Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America
| | | | - Alison A Motsinger-Reif
- Bioinformatics Research Center, North Carolina State University, Raleigh, NC, United States of America.,Department of Statistics, North Carolina State University, Raleigh, NC, United States of America
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Haitjema S, Meddens CA, van der Laan SW, Kofink D, Harakalova M, Tragante V, Foroughi Asl H, van Setten J, Brandt MM, Bis JC, O’Donnell C, Cheng C, Hoefer IE, Waltenberger J, Biessen E, Jukema JW, Doevendans PA, Nieuwenhuis EE, Erdmann J, Björkegren JL, Pasterkamp G, Asselbergs FW, den Ruijter HM, Mokry M. Additional Candidate Genes for Human Atherosclerotic Disease Identified Through Annotation Based on Chromatin Organization. ACTA ACUST UNITED AC 2017; 10:CIRCGENETICS.116.001664. [DOI: 10.1161/circgenetics.116.001664] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 12/12/2016] [Indexed: 11/16/2022]
Abstract
Background—
As genome-wide association efforts, such as CARDIoGRAM and METASTROKE, are ongoing to reveal susceptibility loci for their underlying disease—atherosclerotic disease—identification of candidate genes explaining the associations of these loci has proven the main challenge. Many disease susceptibility loci colocalize with DNA regulatory elements, which influence gene expression through chromatin interactions. Therefore, the target genes of these regulatory elements can be considered candidate genes. Applying these biological principles, we used an alternative approach to annotate susceptibility loci and identify candidate genes for human atherosclerotic disease based on circular chromosome conformation capture followed by sequencing.
Methods and Results—
In human monocytes and coronary endothelial cells, we generated 63 chromatin interaction data sets for 37 active DNA regulatory elements that colocalize with known susceptibility loci for coronary artery disease (CARDIoGRAMplusC4D) and large artery stroke (METASTROKE). By circular chromosome conformation capture followed by sequencing, we identified a physical 3-dimensional interaction with 326 candidate genes expressed in at least 1 of these cell types, of which 294 have not been reported before. We highlight 16 genes based on expression quantitative trait loci.
Conclusions—
Our findings provide additional candidate-gene annotation for 37 disease susceptibility loci for human atherosclerotic disease that are of potential interest to better understand the complex pathophysiology of cardiovascular diseases.
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Monir MM, Zhu J. Comparing GWAS Results of Complex Traits Using Full Genetic Model and Additive Models for Revealing Genetic Architecture. Sci Rep 2017; 7:38600. [PMID: 28079101 PMCID: PMC5227710 DOI: 10.1038/srep38600] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 10/25/2016] [Indexed: 01/09/2023] Open
Abstract
Most of the genome-wide association studies (GWASs) for human complex diseases have ignored dominance, epistasis and ethnic interactions. We conducted comparative GWASs for total cholesterol using full model and additive models, which illustrate the impacts of the ignoring genetic variants on analysis results and demonstrate how genetic effects of multiple loci could differ across different ethnic groups. There were 15 quantitative trait loci with 13 individual loci and 3 pairs of epistasis loci identified by full model, whereas only 14 loci (9 common loci and 5 different loci) identified by multi-loci additive model. Again, 4 full model detected loci were not detected using multi-loci additive model. PLINK-analysis identified two loci and GCTA-analysis detected only one locus with genome-wide significance. Full model identified three previously reported genes as well as several new genes. Bioinformatics analysis showed some new genes are related with cholesterol related chemicals and/or diseases. Analyses of cholesterol data and simulation studies revealed that the full model performs were better than the additive-model performs in terms of detecting power and unbiased estimations of genetic variants of complex traits.
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Affiliation(s)
- Md Mamun Monir
- Institute of Bioinformatics, Zhejiang University, Hangzhou 310058, China
| | - Jun Zhu
- Institute of Bioinformatics, Zhejiang University, Hangzhou 310058, China
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Zhong LY, Cayabyab FS, Tang CK, Zheng XL, Peng TH, Lv YC. Sortilin: A novel regulator in lipid metabolism and atherogenesis. Clin Chim Acta 2016; 460:11-7. [PMID: 27312323 DOI: 10.1016/j.cca.2016.06.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2016] [Revised: 06/07/2016] [Accepted: 06/11/2016] [Indexed: 11/26/2022]
Abstract
Several lines of evidence have shown that SORT1 gene within 1p13.3 locus is an important modulator of the low-density lipoprotein-cholesterol (LDL-C) level and atherosclerosis risk. Here, we summarize the effects of SORT1, which codes for sortilin, on lipid metabolism and development of atherosclerosis and explore the mechanisms underlying sortilin effects on lipid metabolism especially in hepatocytes and macrophages. Recent epidemiological evidence demonstrated that sortilin has been implicated as the causative factor and regulates lipid metabolism in vivo. Hepatic sortilin overexpression leads to both increased and decreased LDL-C levels by several different mechanisms, suggesting the complex roles of sortilin in hepatic lipid metabolism. Macrophage sortilin causes internalization of LDL and probably a reduction in cholesterol efflux, resulting in the intracellular accumulation of excessive lipids. In addition, sortilin deficiency in an atherosclerotic mouse model results in decreased aortic atherosclerotic lesion. Sortilin involves in lipid metabolism, promotes the development of atherosclerosis, and possibly becomes a potential therapeutic target for atherosclerosis treatment.
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Affiliation(s)
- Li-Yuan Zhong
- Laboratory of Clinical Anatomy, University of South China, Hengyang 421001, China
| | - Francisco S Cayabyab
- Department of Surgery, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - Chao-Ke Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang 421001, China
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, The University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada
| | - Tian-Hong Peng
- Laboratory of Clinical Anatomy, University of South China, Hengyang 421001, China.
| | - Yun-Cheng Lv
- Laboratory of Clinical Anatomy, University of South China, Hengyang 421001, China.
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Shahid SU, ᅟ S, Cooper JA, Beaney KE, Li K, Rehman A, Humphries SE. Effect of SORT1, APOB and APOE polymorphisms on LDL-C and coronary heart disease in Pakistani subjects and their comparison with Northwick Park Heart Study II. Lipids Health Dis 2016; 15:83. [PMID: 27112212 PMCID: PMC4845441 DOI: 10.1186/s12944-016-0253-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Accepted: 04/19/2016] [Indexed: 12/26/2022] Open
Abstract
Background Many SNPs have been identified in genes regulating LDL-C metabolism, but whether their influence is similar in subjects from different ethnicities is unclear. Effect of 4 such SNPs on LDL-C and coronary heart disease (CHD) was examined in Pakistani subjects and was compared with middle aged UK men from Northwick Park Heart Study II (NPHSII). Methods One thousand nine hundred sixty-five (1770 non CHD, 195 CHD) UK and 623 (219 non CHD, 404 CHD) Pakistani subjects were enrolled in the study. The SNPs SORT1 rs646776, APOB rs1042031 and APOE rs429358, rs7412 were genotyped by TaqMan/KASPar technique and their gene score was calculated. LDL-C was calculated by Friedewald equation, results were analyzed using SPSS. Results Allele frequencies were significantly different (p = <0.05) between UK and Pakistani subjects. However, the SNPs were associated with LDL-C in both groups. In UK non CHD, UK CHD, Pakistani non CHD and Pakistani CHD respectively, for rs646776, per risk allele increase in LDL-C(mmol/l) was 0.18(0.04), 0.06(0.11), 0.15(0.04) and 0.27(0.06) respectively. For rs1042031, per risk allele increase in LDL-C in four groups was 0.11(0.04), 0.04(0.14), 0.15(0.06) and 0.25(0.09) respectively. For APOE genotypes, compared to Ɛ3, each Ɛ2 decreased LDL-C by 0.11(0.06), 0.07(0.15), 0.20(0.08) and 0.38(0.09), while each Ɛ4 increased LDL-C by 0.43(0.06), 0.39(0.21), 0.19(0.11) and 0.39(0.14) respectively. Overall gene score explained a considerable proportion of sample variance in four groups (3.8 %, 1.26 % 13.7 % and 12.3 %). Gene score in both non-CHD groups was significantly lower than CHD subjects. Conclusions The SNPs show a dose response association with LDL-C levels and risk of CHD in both populations. Electronic supplementary material The online version of this article (doi:10.1186/s12944-016-0253-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Saleem Ullah Shahid
- Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan.
| | - Shabana ᅟ
- Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan
| | - Jackie A Cooper
- Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, University College London, London, WC1E6JF, UK
| | - Katherine E Beaney
- Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, University College London, London, WC1E6JF, UK
| | - Kawah Li
- Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, University College London, London, WC1E6JF, UK
| | - Abdul Rehman
- Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan
| | - Stephen Eric Humphries
- Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, University College London, London, WC1E6JF, UK
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Dai X, Wiernek S, Evans JP, Runge MS. Genetics of coronary artery disease and myocardial infarction. World J Cardiol 2016; 8:1-23. [PMID: 26839654 PMCID: PMC4728103 DOI: 10.4330/wjc.v8.i1.1] [Citation(s) in RCA: 124] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Revised: 10/18/2015] [Accepted: 11/10/2015] [Indexed: 02/06/2023] Open
Abstract
Atherosclerotic coronary artery disease (CAD) comprises a broad spectrum of clinical entities that include asymptomatic subclinical atherosclerosis and its clinical complications, such as angina pectoris, myocardial infarction (MI) and sudden cardiac death. CAD continues to be the leading cause of death in industrialized society. The long-recognized familial clustering of CAD suggests that genetics plays a central role in its development, with the heritability of CAD and MI estimated at approximately 50% to 60%. Understanding the genetic architecture of CAD and MI has proven to be difficult and costly due to the heterogeneity of clinical CAD and the underlying multi-decade complex pathophysiological processes that involve both genetic and environmental interactions. This review describes the clinical heterogeneity of CAD and MI to clarify the disease spectrum in genetic studies, provides a brief overview of the historical understanding and estimation of the heritability of CAD and MI, recounts major gene discoveries of potential causal mutations in familial CAD and MI, summarizes CAD and MI-associated genetic variants identified using candidate gene approaches and genome-wide association studies (GWAS), and summarizes the current status of the construction and validations of genetic risk scores for lifetime risk prediction and guidance for preventive strategies. Potential protective genetic factors against the development of CAD and MI are also discussed. Finally, GWAS have identified multiple genetic factors associated with an increased risk of in-stent restenosis following stent placement for obstructive CAD. This review will also address genetic factors associated with in-stent restenosis, which may ultimately guide clinical decision-making regarding revascularization strategies for patients with CAD and MI.
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Affiliation(s)
- Xuming Dai
- Xuming Dai, Szymon Wiernek, Marschall S Runge, Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Szymon Wiernek
- Xuming Dai, Szymon Wiernek, Marschall S Runge, Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - James P Evans
- Xuming Dai, Szymon Wiernek, Marschall S Runge, Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Marschall S Runge
- Xuming Dai, Szymon Wiernek, Marschall S Runge, Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
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Frånberg M, Gertow K, Hamsten A, PROCARDIS consortium, Lagergren J, Sennblad B. Discovering Genetic Interactions in Large-Scale Association Studies by Stage-wise Likelihood Ratio Tests. PLoS Genet 2015; 11:e1005502. [PMID: 26402789 PMCID: PMC4581725 DOI: 10.1371/journal.pgen.1005502] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 08/14/2015] [Indexed: 01/26/2023] Open
Abstract
Despite the success of genome-wide association studies in medical genetics, the underlying genetics of many complex diseases remains enigmatic. One plausible reason for this could be the failure to account for the presence of genetic interactions in current analyses. Exhaustive investigations of interactions are typically infeasible because the vast number of possible interactions impose hard statistical and computational challenges. There is, therefore, a need for computationally efficient methods that build on models appropriately capturing interaction. We introduce a new methodology where we augment the interaction hypothesis with a set of simpler hypotheses that are tested, in order of their complexity, against a saturated alternative hypothesis representing interaction. This sequential testing provides an efficient way to reduce the number of non-interacting variant pairs before the final interaction test. We devise two different methods, one that relies on a priori estimated numbers of marginally associated variants to correct for multiple tests, and a second that does this adaptively. We show that our methodology in general has an improved statistical power in comparison to seven other methods, and, using the idea of closed testing, that it controls the family-wise error rate. We apply our methodology to genetic data from the PROCARDIS coronary artery disease case/control cohort and discover three distinct interactions. While analyses on simulated data suggest that the statistical power may suffice for an exhaustive search of all variant pairs in ideal cases, we explore strategies for a priori selecting subsets of variant pairs to test. Our new methodology facilitates identification of new disease-relevant interactions from existing and future genome-wide association data, which may involve genes with previously unknown association to the disease. Moreover, it enables construction of interaction networks that provide a systems biology view of complex diseases, serving as a basis for more comprehensive understanding of disease pathophysiology and its clinical consequences.
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Affiliation(s)
- Mattias Frånberg
- Atherosclerosis Research Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Numerical Analysis and Computer Science, Stockholm University, Stockholm, Sweden
- Science for Life Laboratory, Stockholm, Sweden
- * E-mail:
| | - Karl Gertow
- Atherosclerosis Research Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Anders Hamsten
- Atherosclerosis Research Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | | | - Jens Lagergren
- School of Computer Science and Communications, KTH Royal Institute of Technology, Science for Life Laboratory, Swedish e-Science Research Centre, Stockholm, Sweden
| | - Bengt Sennblad
- Atherosclerosis Research Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
- Science for Life Laboratory, Stockholm, Sweden
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ABE SHINTARO, TOKORO FUMITAKA, MATSUOKA REIKO, ARAI MASAZUMI, NODA TOSHIYUKI, WATANABE SACHIRO, HORIBE HIDEKI, FUJIMAKI TETSUO, OGURI MITSUTOSHI, KATO KIMIHIKO, MINATOGUCHI SHINYA, YAMADA YOSHIJI. Association of genetic variants with dyslipidemia. Mol Med Rep 2015; 12:5429-36. [DOI: 10.3892/mmr.2015.4081] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 06/06/2015] [Indexed: 11/06/2022] Open
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Pal LR, Yu CH, Mount SM, Moult J. Insights from GWAS: emerging landscape of mechanisms underlying complex trait disease. BMC Genomics 2015; 16 Suppl 8:S4. [PMID: 26110739 PMCID: PMC4480957 DOI: 10.1186/1471-2164-16-s8-s4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND There are now over 2000 loci in the human genome where genome wide association studies (GWAS) have found one or more SNPs to be associated with altered risk of a complex trait disease. At each of these loci, there must be some molecular level mechanism relevant to the disease. What are these mechanisms and how do they contribute to disease? RESULTS Here we consider the roles of three primary mechanism classes: changes that directly alter protein function (missense SNPs), changes that alter transcript abundance as a consequence of variants close-by in sequence, and changes that affect splicing. Missense SNPs are divided into those predicted to have a high impact on in vivo protein function, and those with a low impact. Splicing is divided into SNPs with a direct impact on splice sites, and those with a predicted effect on auxiliary splicing signals. The analysis was based on associations found for seven complex trait diseases in the classic Wellcome Trust Case Control Consortium (WTCCC1) GWA study and subsequent studies and meta-analyses, collected from the GWAS catalog. Linkage disequilibrium information was used to identify possible candidate SNPs for involvement in disease mechanism in each of the 356 loci associated with these seven diseases. With the parameters used, we find that 76% of loci have at least of these mechanisms. Overall, except for the low incidence of direct impact on splice sites, the mechanisms are found at similar frequencies, with changes in transcript abundance the most common. But the distribution of mechanisms over diseases varies markedly, as does the fraction of loci with assigned mechanisms. Many of the implicated proteins have previously been suggested as relevant, but the specific mechanism assignments are new. In addition, a number of new disease relevant proteins are proposed. CONCLUSIONS The high fraction of GWAS loci with proposed mechanisms suggests that these classes of mechanism play a major role. Other mechanism types, such as variants affecting expression of genes remote in the DNA sequence, will contribute in other loci. Each of the identified putative mechanisms provides a hypothesis for further investigation.
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Affiliation(s)
- Lipika R Pal
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD, USA
| | - Chen-Hsin Yu
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD, USA
- Molecular and Cellular Biology Program, University of Maryland, College Park, MD, USA
| | - Stephen M Mount
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA
- Center for Bioinformatics and Computational Biology, University of Maryland at College Park, College Park, MD, USA
| | - John Moult
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD, USA
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA
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Sortilin, Encoded by the Cardiovascular Risk Gene SORT1, and Its Suggested Functions in Cardiovascular Disease. Curr Atheroscler Rep 2015; 17:496. [DOI: 10.1007/s11883-015-0496-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Wang XJ, Zhang DL, Xu ZG, Ma ML, Wang WB, Li LL, Han XL, Huo Y, Yu X, Sun JP. Understanding cadherin EGF LAG seven-pass G-type receptors. J Neurochem 2014; 131:699-711. [PMID: 25280249 DOI: 10.1111/jnc.12955] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 09/05/2014] [Accepted: 09/22/2014] [Indexed: 12/21/2022]
Abstract
The cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptors (CELSRs) are a special subgroup of adhesion G protein-coupled receptors, which are pivotal regulators of many biologic processes such as neuronal/endocrine cell differentiation, vessel valve formation, and the control of planar cell polarity during embryonic development. All three members of the CELSR family (CELSR1-3) have large ecto-domains that form homophilic interactions and encompass more than 2000 amino acids. Mutations in the ecto-domain or other gene locations of CELSRs are associated with neural tube defects and other diseases in humans. Celsr knockout (KO) animals have many developmental defects. Therefore, specific agonists or antagonists of CELSR members may have therapeutic potential. Although significant progress has been made regarding the functions and biochemical properties of CELSRs, our knowledge of these receptors is still lacking, especially considering that they are broadly distributed but have few characterized functions in a limited number of tissues. The dynamic activation and inactivation of CELSRs and the presence of endogenous ligands beyond homophilic interactions remain elusive, as do the regulatory mechanisms and downstream signaling of these receptors. Given this motivation, future studies with more advanced cell biology or biochemical tools, such as conditional KO mice, may provide further insights into the mechanisms underlying CELSR function, laying the foundation for the design of new CELSR-targeted therapeutic reagents. The cadherin EGF LAG seven-pass G-type receptors (CELSRs) are a special subgroup of adhesion G protein-coupled receptors (GPCRs), which have large ecto-domains that form homophilic interactions and encompass more than 2000 amino acids. Recent studies have revealed that CELSRs are pivotal regulators of many biological processes, such as neuronal/endocrine cell differentiation, vessel valve formation and the control of planar cell polarity during embryonic development.
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Affiliation(s)
- Xiao-Jing Wang
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, China; Department of Cell Biology, Shandong University School of Medicine, Jinan, Shandong, China; Shandong Provincial School Key laboratory for Protein Science of Chronic Degenerative Diseases, Jinan, Shandong, China
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