Abstract 2414: Genome-wide Association Analyses From The Vitamin Intervention For Stroke Prevention (visp) Trial Identify Genetic Loci That Influence Post-stroke Measures Of Inflammation And Thrombosis
The Vitamin Intervention for Stroke Prevention (VISP) trial was a multi-center, controlled, double blinded clinical trial, designed to determine whether the daily intake of high dose folic acid, vitamins B6 and B12 reduced recurrent cerebral infarction. As part of GARNET (the Genomics and Randomized Trials Network), we have performed a Genome-Wide Association Study (GWAS), using the Illumina Omni 1M SNP platform in 2,100 ischemic stroke patients from VISP. Extensive quality control (QC) measures were performed, resulting in a total of 737,081 SNPs for analysis. We have performed GWA analyses for baseline quantitative measures of creatinine, total cholesterol (TC), high density lipoprotein (HDL), triglycerides (TG), C-reactive protein (CRP), Factor1+2 thrombin-antithrombin (TAT), tissue plasminogen activator (tPA), thrombomodulin (TM) and von Willebrand factor (vWF), using linear regression approaches implemented in PLINK. Principal component analysis (PCA), implemented in KING, was utilized to address confounders due to population substructure. Inverse normal transformation was performed for each of the quantitative traits, prior to analysis. Genome wide association analyses were performed using age, sex and the top 10 principal components as covariates. There is no inflation in our GWAS scan results (GC lambda ≤ 1.012 in all scans). We observed three associated loci that exceed genome wide significance (≤6.8×10-8): in or near the CETP gene for HDL (6.5×10-10), the CRP gene for CRP (7.4×10-10), and at the ABO locus for vWF (8.7×10-31). The most strongly associated SNPs for other traits were closest to the following genes: GABRA3 for creatinine (rs994424, 5.7×10-6), SPATA13 for TC (rs9553189, 3.2×10-7), between ARMCX2 and NXF5 genes on the X chromosome for TG (rs2213369, 1.7×10-6); the ZIC4 gene for TAT (rs17565826, 4.1×10-6); LOC283089 for tPA (rs3011337, 3.6×10-6); and JAZF1 for TM (rs10258132, 1.1×10-6). Putative novel associations with these traits will require confirmation in larger independent samples. Our GWAS scan has successfully replicated associations for SNPs in the CETP, CRP and ABO genes for HDL, CRP and vWF respectively in an ischemic stroke population.
- © 2012 by American Heart Association, Inc.