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Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.

ABSTRACT: BACKGROUND AND PURPOSE:Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. METHODS:Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. RESULTS:Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)). CONCLUSIONS:Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

SUBMITTER: Dichgans M

PROVIDER: S-EPMC4112102 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.

Dichgans Martin M Malik Rainer R König Inke R IR Rosand Jonathan J Clarke Robert R Gretarsdottir Solveig S Thorleifsson Gudmar G Mitchell Braxton D BD Assimes Themistocles L TL Levi Christopher C O'Donnell Christopher J CJ Fornage Myriam M Thorsteinsdottir Unnur U Psaty Bruce M BM Hengstenberg Christian C Seshadri Sudha S Erdmann Jeanette J Bis Joshua C JC Peters Annette A Boncoraglio Giorgio B GB März Winfried W Meschia James F JF Kathiresan Sekar S Ikram M Arfan MA McPherson Ruth R Stefansson Kari K Sudlow Cathie C Reilly Muredach P MP Thompson John R JR Sharma Pankaj P Hopewell Jemma C JC Chambers John C JC Watkins Hugh H Rothwell Peter M PM Roberts Robert R Markus Hugh S HS Samani Nilesh J NJ Farrall Martin M Schunkert Heribert H

Stroke 20131121 1

<h4>Background and purpose</h4>Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.<h4>Methods</h4>Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed com ...[more]

PMID: 24262325

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Project description:Our previous studies identified nine genes and chromosomal region 3q28 as susceptibility loci for myocardial infarction, ischemic stroke or chronic kidney disease by genome-wide or candidate gene association studies. As coronary artery disease (CAD) and ischemic stroke may share genetic architecture, certain genetic variants may confer susceptibility to the two diseases. The present study examined the association of 13 polymorphisms at these 10 loci with the prevalence of CAD or ischemic stroke in community-dwelling individuals, with the aim of identifying genetic variants that confer susceptibility to the two conditions. Study subjects (170 with CAD, 117 with ischemic stroke and 5,718 controls) were recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited for an annual health checkup and they were followed up each year (mean follow-up period, 5 years). Longitudinal analysis with a generalized estimating equation, and with adjustment for age, gender, body mass index, smoking status, the prevalence of hypertension, diabetes mellitus and dyslipidemia and the serum concentration of creatinine, revealed that rs2074380 (G→A) and rs2074381 (A→G) of the α-kinase 1 (ALPK1) gene and rs8089 (T→G) of the thrombospondin 2 (THBS2) gene were significantly (P<2×10-16) associated with the prevalence of CAD, with the AA genotype of rs2074380 and GG genotypes of rs2074381 and rs8089 being protective against this condition. Similar analysis revealed that rs9846911 (A→G) at chromosome 3q28, rs2074381 of ALPK1, rs8089 of THBS2 and rs6046 (G→A) of the coagulation factor VII gene were significantly (P<2×10-16) associated with the prevalence of ischemic stroke, with the GG genotypes of rs9846911, rs2074381 and rs8089 and the AA genotype of rs6046 being protective against this condition. ALPK1 and THBS2 may thus be susceptibility loci for CAD and ischemic stroke.

Dataset Information

Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.

Publications

Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.

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