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Genomics of Incident Ischemic Stroke Events, Stroke and Cardiovascular Disease

Reporter: Aviva Lev-Ari, PhD, RN

Associations Between Incident Ischemic Stroke Events and Stroke and Cardiovascular Disease-Related Genome-Wide Association Studies Single Nucleotide Polymorphisms in the Population Architecture Using Genomics and Epidemiology Study

Cara L. Carty, PhD, Petra Bůžková, PhD, Myriam Fornage, PhD, Nora Franceschini, MD, Shelley Cole, PhD, Gerardo Heiss, MD, PhD, Lucia A. Hindorff, PhD, MPH, Barbara V. Howard, PhD, Sue Mann, MPH, Lisa W. Martin, MD, Ying Zhang, PhD, Tara C. Matise, PhD, Ross Prentice, PhD, Alexander P. Reiner, MD, MS and Charles Kooperberg, PhD

Author Affiliations

From the Public Health Sciences, Fred Hutchinson Cancer Research Center (C.L.C., S.M., R.P., C.K.); Department of Biostatistics, University of Washington, Seattle, WA (P.B.); Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX (M.F.); Division of Epidemiology, School of Public Health, University of Texas Health Sciences Center, Houston, TX (M.F.); Department of Epidemiology, University of North Carolina, Chapel Hill, NC (N.F., G.H.); Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX (S.C.); Office of Population Genomics, National Human Genome Research Institute, Bethesda, MD (L.A.H.); Medstar Health Research Institute, Washington, DC (B.V.H.); George Washington University School of Medicine, Washington, DC (B.V.H., L.W.M.); University of Oklahoma Health Sciences Center, Oklahoma City, OK (Y.Z.); Department of Genetics, Rutgers University, Piscataway, NJ (T.C.M.); Department of Epidemiology, University of Washington, Seattle, WA (A.P.R.).

Correspondence to Dr Cara L. Carty, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N./M3-A410, Seattle, WA 98109. E-mail ccarty@fhcrc.org

Abstract

Background—Genome-wide association studies (GWAS) have identified loci associated with ischemic stroke (IS) and cardiovascular disease (CVD) in European-descent individuals, but their replication in different populations has been largely unexplored.

Methods and Results—Nine single nucleotide polymorphisms (SNPs) selected from GWAS and meta-analyses of stroke, and 86 SNPs previously associated with myocardial infarction and CVD risk factors, including blood lipids (high density lipoprotein [HDL], low density lipoprotein [LDL], and triglycerides), type 2 diabetes, and body mass index (BMI), were investigated for associations with incident IS in European Americans (EA) N=26 276, African-Americans (AA) N=8970, and American Indians (AI) N=3570 from the Population Architecture using Genomicsand Epidemiology Study. Ancestry-specific fixed effects meta-analysis with inverse variance weighting was used to combine study-specific log hazard ratios from Cox proportional hazards models. Two of 9 stroke SNPs (rs783396 and rs1804689) were associated with increased IS hazard in AA; none were significant in this large EA cohort. Of 73 CVD risk factor SNPs tested in EA, 2 (HDL and triglycerides SNPs) were associated with IS. In AA, SNPs associated with LDL, HDL, and BMI were significantly associated with IS (3 of 86 SNPs tested). Out of 58 SNPs tested in AI, 1 LDL SNP was significantly associated with IS.

Conclusions—Our analyses showing lack of replication in spite of reasonable power for many stroke SNPs and differing results by ancestry highlight the need to follow up on GWAS findings and conduct genetic association studies in diverse populations. We found modest IS associations with BMI and lipids SNPs, though these findings require confirmation.

SOURCE:

Circulation: Cardiovascular Genetics.2012; 5: 210-216