Association Between Serum Folate Concentrations and 10-Year Stroke Risk in a Prospective Community Cohort: Mediation and Interaction Analyses

The relationship between folate concentrations and stroke risk remains unestablished, and the mediation effect of homocysteine (Hcy) and interaction effect of methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has yet to be investigated. This cohort study involved 4903 subjects derived from a Chinese community population. The association between folate and first stroke was examined in Cox proportional hazard regression models. The mediation analyses involving Hcy and the undiscovered modification of the MTHFR C677T genotype were assessed. The mean (SD) age of subjects was 56.7 (8.8) years old, and 37.0% were male. A total of 407 strokes, 375 ischemic strokes and 47 hemorrhagic strokes occurred during the mean (SD) follow-up of 9.3 (1.8) years. The participants in the highest folate quartile (>= 8.2 ng/mL) exhibited a lower stroke risk compared to those in the lowest quartile (hazard ratio [HR]: 0.68, 95% confidence interval [CI]: 0.50-0.93, p = 0.017; p for trend = 0.009). Hcy significantly mediated 14.51% of the relationship between folate and stroke in the fully adjusted model. Only in individuals with the MTHFR 677CC genotype but not CT/TT genotype was folate adversely correlated with stroke (HR: 0.88, 95% CI: 0.79-0.97, p for interaction = 0.026) and ischemic stroke (HR: 0.88, 95% CI: 0.80-0.98, p for interaction = 0.035). Insufficient folate concentrations were associated with a heightened 10-year stroke risk, in which Hcy concentrations played a crucial mediating role. MTHFR C677T gene polymorphism could potentially modify the folate-stroke relationship.