Interaction of serum vitamin B ₁₂ and folate with MTHFR genotypes on risk of ischemic stroke

Objective We evaluated the interaction of serum folate and vitamin B₁₂ with methylenetetrahydrofolate reductase (MTHFR) C677T genotypes on the risk of first ischemic stroke and on the efficacy of folic acid treatment in prevention of first ischemic stroke. Methods A total of 20,702 hypertensive adults were randomized to a double-blind treatment of daily enalapril 10 mg and folic acid 0.8 mg or enalapril 10 mg alone. Participants were followed up every 3 months. Results Median values of folate and B₁₂ concentrations at baseline were 8.1 ng/mL and 280.2 pmol/L, respectively. Over a median of 4.5 years, among those not receiving folic acid, participants with baseline serum B₁₂ or serum folate above the median had a significantly lower risk of first ischemic stroke (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57–0.96), especially in those with MTHFR 677 CC genotype (wild-type) (HR, 0.49; 95% CI, 0.31–0.78). Folic acid treatment significantly reduced the risk of first ischemic stroke in participants with both folate and B₁₂ below the median (2.3% in enalapril-folic acid group vs 3.6% in enalapril-only group; HR, 0.62; 95% CI, 0.46–0.86), particularly in MTHFR 677 CC carriers (1.6% vs 4.9%; HR, 0.24; 95% CI, 0.11–0.55). However, TT homozygotes responded better with both folate and B₁₂ levels above the median (HR, 0.28; 95% CI, 0.10–0.75). Conclusions The risk of first ischemic stroke was significantly higher in hypertensive patients with low levels of both folate and B₁₂. Effect of folic acid treatment was greatest in patients with low folate and B₁₂ with the CC genotype, and with high folate and B₁₂ with the TT genotype.