Sequence variation in the gene encoding soluble epoxide hydrolase (EPHX2) is associated with increased susceptibility to ischemic stroke in a central european population

Background and purpose: Recent evidence suggests that genetic variation in the EPHX2 gene region modifies individual risk of ischemic stroke. The role of EPHX2 has not yet been explored with regard to stroke subtypes, however. Our goal was to replicate the original findings in a large and well-characterized sample of central European patients; additionally, we set out to examine the role of EPHX2 with regard to specific stroke subtypes.

Methods: We genotyped 26 single nucleotide polymorphisms (SNPs) in the EPHX2 gene region in a population of 601 stroke patients and 736 unrelated matched controls using a case-control design. With regard to stroke etiology, all patients were subtyped according to the Trial of Org 10172 in Acute Stroke Treatment Trial (TOAST) classification system. Individual SNPs were analyzed as well as haplotypes using a sliding-window approach.

Results: Three SNPs including one non-synonymous variant showed nominally significant associations with an increased risk for overall ischemic stroke (allelic models; all p≤0.005). After correction for multiple testing, one association retained a level of statistical significance (corrected p-value=0.020). All three SNPs that had shown associations in the overall sample were also associated with a) large vessel stroke and b) stroke of undetermined etiology but not with any other stroke subtypes.

Conclusions: Our data provide further evidence that genetic variation in the EPHX2 gene region modifies individual susceptibility to ischemic stroke. The results of previous studies were extended by the analysis of stroke subtypes, which suggests that the association is primarily mediated by large vessel disease. Together with findings in coronary heart disease, these results emphasize the importance of EPHX2 in the pathogenesis of atherosclerosis and cardiovascular disease.