The Effect of SNPs, Their Haplotypes, and Gene-Environment Interactions on the Risk of Atherothrombotic Stroke Among the Chinese Population

Ischemic stroke (IS) is a severe and complex disorder with high morbidity and mortality rates and it has been associated with both environmental and genetic predisposing factors. The purpose of this study was to evaluate the association of the alpha-1-microglobulin/bikunin precursor () gene polymorphisms with IS and any possible interactions between specific alleles and traditional risk factors among a Han Chinese cohort. We conducted a candidate gene study designed to characterize nine (9) single nucleotide polymorphisms (SNPs) of the gene among 195 patients with atherothrombotic stroke (ATS) (a major subtype of IS) and 184 nonstroke controls. Allelic and genotypic frequency differences were evaluated using a logistic regression model. False discovery rate (FDR) correction for multiple comparisons was used. The interactional analyses were performed using the multifactor dimensionality reduction test. We found an association between the rs2567698 CC genotype (odds ratio [OR], 95% confidence interval [CI]: 2.176, 1.159-4.086) and the T allele (OR, 95% CI: 0.654, 0.446-0.960) with risk of ATS in men. However, these associations did not survive FDR correction. In haplotype analyses, the GCCCCCCCC haplotype had a higher frequency (OR, 95% CI: 2.191, 1.048-4.580) in ATS in the ≥45 years of age subgroup, whereas the GCCTCCCCC haplotype decreased the risk for ATS (OR, 95% CI: 0.543, 0.345-0.853) in men. In addition, we also found interactions for ATS risk between SNPs in the gene and modifiable risk factors for ATS, including: rs11788411 and hypertension in the overall population and women; rs2251680 and hypertension in subjects aged 45 years and older, as well as the interaction among hypertension and the rs2567698 and rs10817564 genotypes in men. Our results show a possible association between SNP haplotypes and gene-environment interactions with ATS susceptibility in a Han Chinese cohort.