Variants in the Atherogenic ALOX5AP, THBD, and KNG1 Genes Potentiate the Risk of Ischemic Stroke via a Genetic Main Effect and Epistatic Interactions in a Chinese Population

Abstract

Ischemic stroke (IS) is a multifactorial disease that displays a strong genetic predisposition. However, the genetic architecture of IS has yet to be fully elucidated. It was hypothesized that epistasis between genes in multiple atherothrombotic pathways may play a vital role in determining the susceptibility to IS. The aim of the present study was to investigate the contributions of the hypothesized genetic factors to IS and the interactions between these genetic factors in a Chinese population. In this study, 351 cases with IS and 417 control subjects from a Chinese population were genotyped for single-nucleotide polymorphisms (SNPs) in 12 genes hypothesized to be involved in atherosclerosis, coagulation, and related pathways. We examined SNP main effects and epistatic interactions between these polymorphic loci. rs710446 of the KNG1 gene was associated with IS susceptibility based on an additive genetic model (rs710446: P = .012; odds ratio [OR], 1.247; 95% confidence interval [CI], 1.050-1.481) after adjusting for covariates. Furthermore, an epistatic interaction between the ALOX5AP, THBD, and KNG1 gene was also identified in association with stroke susceptibility (P < .001 after 1000 permutations). Based on the chi-squared test, the OR of the high-risk combination of the three-locus model increased the risk of IS by 2.53-fold (95% CI, 1.60-4.01; P < .0001). Our findings support the association of the epistatic interactions of ALOX5AP, THBD, and KNG1 and present novel evidence for the main effect of KNG1 gene on IS susceptibility, suggesting a modulation of stroke risk by a genetic main effect and gene-gene interactions.