Genetic Variation in Platelet Function as a Risk Factor for Ischemic Stroke

Abstract

Background: Ischemic stroke is a leading cause of disability and mortality in the US. Studies in twins and families suggest that ischemic stroke is genetically controlled; however, the genetic determinants remain largely unknown. One mechanism through which genes might influence stroke susceptibility is through their effects on platelet function. Antiplatelet medications have been shown effective in reducing the risk of ischemic stroke and several studies have shown platelet aggregation traits to be heritable. Therefore, we sought to identify loci associated with platelet aggregation and test them for association with ischemic stroke. Methods: Using data from two genetic studies of platelet aggregation in the Amish, we performed principal components analyses to reduce the dimensionality of the data into a smaller number of phenotypes. We assessed the properties of resulting components by identifying their correlates, estimated the genetic contributions to each and assessed evidence for pleiotropy among them. We then performed genetic association analyses on resulting traits to identify associated loci. Top loci were then tested for association with ischemic stroke using a case control study in young adults. Results: Platelet aggregation traits were reduced to three principal components in our first Amish study and one component in the second study. All were heritable and the first and third components showed evidence for pleiotropy in our first Amish study (r<subscript>genetic=-0.45). Previously identified covariates were also associated with our principal components. At the genome-wide α level of significance, three SNPs were significantly associated with the third principal component (rs12618009 p=5.0 x 10<superscript>-9; rs1527075 p=5.9 x 10<superscript>-8; rs1684918 p=7.0 x 10<superscript>-8. The first component was also associated with rs12041331 (PEAR1) (p=0.002) in the first Amish study. Of the SNPs tested for association with ischemic stroke, rs12041331 was significantly associated with large artery ischemic stroke (OR=2.04, 95% CI=1.28-3.23). Conclusions: One strategy for identifying stroke susceptibility genes is to study intermediate phenotypes. Using this approach we created novel platelet aggregation traits using principal components analysis and identified several associated loci. When tested for association with ischemic stroke, rs12041331 was significantly associated with large artery ischemic stroke.