Genetic variants of vitamin D receptor and susceptibility to ischemic stroke.

Vitamin D receptor (VDR) is a potential candidate for cardiovascular disease. To date the genetic association of VDR with ischemic stroke has not been explored. In the present study we aimed to evaluate the association between VDR gene variants and ischemic stroke in Asian Indian population. Overall, 557 subjects were investigated that included 313 ischemic stroke patients and 244 control subjects. Four single nucleotide polymorphisms of the VDR gene termed as Fok I, Apa I, Taq I and Bsm I were genotyped by using PCR-RFLP method. The genotype distribution of Bsm I polymorphism was found to deviate from the Hardy-Weinberg equilibrium in control subjects, and hence excluded from the study. Apa I and Taq I polymorphisms were not found to be associated with ischemic stroke. However, presence of ff genotype of Fok I was found to confer 2.97-fold risk of ischemic stroke (95% CI=1.16-7.63, P=0.02) as compared to FF genotype. This association was found to be independent of various demographic and important biochemical covariates including age, gender, smoking, alcohol intake, BMI, and serum glucose, lipid profile, insulin and HOMA-IR, 25-hydroxyvitamin D and plasma NOx levels [OR=2.27, 95% CI=1.25-4.09, P=0.01]. However, adjustment for lipid metabolites attenuated the genetic association [OR=1.68, 95% CI=0.75-3.78, P=0.21]. Fok I polymorphism was also found to be associated with total cholesterol levels; ff genotype carriers were found to have significantly higher cholesterol levels (203.56 ± 30.50mg/dl) as compared to FF carriers (177.38 ± 47.90 mg/dl) (P=0.04). On stratification by gender the genetic association between Fok I polymorphism and ischemic stroke remained significant in females only (OR=2.28, 95% CI=1.15-4.53, P=0.02). This genetic association was also found to attenuate on adjustment with lipid variables. In the present study we could associate the only known functional polymorphism of VDR i.e., Fok I, with ischemic stroke in a gender specific manner. Adjustment with lipid variables was found to attenuate this association indicating that impaired lipid metabolism may be the underlying mechanism of action of this polymorphism which leads to an increase in the risk of ischemic stroke. Further larger scale validations in other population are warranted in other population.