Interaction of serum Vitamin B₁₂and folate with MTHFR genotypes on risk of ischemic stroke

ObjectiveWe 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.MethodsA 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.ResultsMedian 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).ConclusionsThe 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.