Interaction Between Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphisms and Environment with Susceptibility to Ischemic Stroke in Chinese Population.

Aims: To investigate the association of several single-nucleotide polymorphisms (SNPs) within methylenetetrahydrofolate reductase (MTHFR) gene, and additional gene-environment interaction with ischemic stroke (IS) risk.

Methods: Testing for Hardy-Weinberg equilibrium in controls was conducted using SNPstats (online software: http://bioinfo.iconcologia.net/SNPstats). Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among four SNPs within MTHFR gene and smoking or alcohol drinking.

Results: The frequency of the rs4846049-A allele was 28.6% in IS patients and 19.1% in normal controls, in addition, the frequency of the rs3737967-T allele was 27.9% in IS patients and 20.3% in normal controls, which was also indicating a statistically significant difference. The rs4846049-A and rs3737967-T were associated with an increased risk of IS risk; adjusted odds ratios (ORs) (95% confidence interval [CI]) were 1.76 (1.28-2.13) and 1.51 (1.13-1.97), respectively. GMDR model found significant gene-alcohol drinking interaction combination, but no significant gene-tobacco smoking interaction combinations. In order to obtain the odds ratios and 95% CI for the joint effects of gene-alcohol drinking on IS, we conducted stratified analysis for interaction effect using logistic regression. We found that alcohol drinkers with rs4846049-CA/AA genotype also have the highest IS risk, compared with never drinkers with rs4846049-CC genotype, OR (95% CI) = 3.12 (1.83-4.45), after adjustment for age, smoke, and smoking status.

Conclusions: The rs4846049-A and rs3737967-T, gene-environment interaction between rs1764391 and rs918592, gene-environment interaction between rs4846049 and alcohol drinking were all associated with increased IS risk.