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Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms.

ABSTRACT: Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

SUBMITTER: Howson JMM

PROVIDER: S-EPMC5555387 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms.

Howson Joanna M M JMM Zhao Wei W Barnes Daniel R DR Ho Weang-Kee WK Young Robin R Paul Dirk S DS Waite Lindsay L LL Freitag Daniel F DF Fauman Eric B EB Salfati Elias L EL Sun Benjamin B BB Eicher John D JD Johnson Andrew D AD Sheu Wayne H H WHH Nielsen Sune F SF Lin Wei-Yu WY Surendran Praveen P Malarstig Anders A Wilk Jemma B JB Tybjærg-Hansen Anne A Rasmussen Katrine L KL Kamstrup Pia R PR Deloukas Panos P Erdmann Jeanette J Kathiresan Sekar S Samani Nilesh J NJ Schunkert Heribert H Watkins Hugh H Do Ron R Rader Daniel J DJ Johnson Julie A JA Hazen Stanley L SL Quyyumi Arshed A AA Spertus John A JA Pepine Carl J CJ Franceschini Nora N Justice Anne A Reiner Alex P AP Buyske Steven S Hindorff Lucia A LA Carty Cara L CL North Kari E KE Kooperberg Charles C Boerwinkle Eric E Young Kristin K Graff Mariaelisa M Peters Ulrike U Absher Devin D Hsiung Chao A CA Lee Wen-Jane WJ Taylor Kent D KD Chen Ying-Hsiang YH Lee I-Te IT Guo Xiuqing X Chung Ren-Hua RH Hung Yi-Jen YJ Rotter Jerome I JI Juang Jyh-Ming J JJ Quertermous Thomas T Wang Tzung-Dau TD Rasheed Asif A Frossard Philippe P Alam Dewan S DS Majumder Abdulla Al Shafi AAS Di Angelantonio Emanuele E Chowdhury Rajiv R Chen Yii-Der Ida YI Nordestgaard Børge G BG Assimes Themistocles L TL Danesh John J Butterworth Adam S AS Saleheen Danish D

Nature genetics 20170522 7

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS ...[more]

PMID: 28530674

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Project description:Coronary artery disease (CAD) is the leading cause of mortality and morbidity driven by both genetic and environmental risk factors. Meta-analyses of genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with CAD and myocardial infarction (MI) susceptibility in multi-ethnic populations. The majority of these variants reside in non-coding regulatory regions and are co-inherited with hundreds of candidate regulatory SNPs. Herein, we use integrative genomic, epigenomic, and transcriptomic fine-mapping in human coronary artery smooth muscle cells (HCASMC) and tissues to identify causal regulatory variation and mechanisms responsible for CAD associations. Using these genome-wide maps we prioritize 65 candidate variants and perform allele-specific binding and expression analyses on 7 top candidates. We validate our findings in two independent cohorts of diseased human arterial expression quantitative trait loci (eQTL), which together demonstrate fundamental links between CAD associations and regulatory function in the appropriate disease context. We performed ATAC-seq, ChIP-seq, and RNA-seq on human coronary artery smooth muscle cells grown in SmGM-2 Smooth Muscle Growth Medium-2 including hEGF, insulin, hFGF-B and FBS, but without antibiotics (Lonza, #CC-3182). For ATAC-seq and RNA-seq we performed stimulations with growth factors (TGF-B1, PDGF-BB, PDGF-DD) versus serum-free control. We conducted two biological replicates for each condition using independent donors. For ATAC-seq experiments, sequencing was completed on an Illumina Hiseq 2500, paired-end 50bp reads. For ChIP-seq we performed immunoprecipitations using H3K27ac (Abcam ab4729). We conducted two biological replicates using HCASMC from independent donors, and also did an IgG control for these studies. For RNA-seq we also conducted two replicates using HCASMC from independent donors. For both ChIP-seq and RNA-seq experiments, sequencing was completed on an Illumina HiSeq 2500, paired-end 100bp reads. We also performed ex-vivo ATAC-seq on frozen tissues (isolated media) from normal and atherosclerotic human coronary arteries, using three independent donors for each. Sequencing was also completed on an Illumina HiSeq 2500, paired end 50bp reads.

Dataset Information

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms.

Publications

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms.

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