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 (<i>MTHFR</i>) <i>C677T</i> 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 <i>MTHFR C677T</i> 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, <i>p</i> = 0.017; <i>p</i> 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 <i>MTHFR 677CC</i> genotype but not <i>CT</i>/<i>TT</i> genotype was folate adversely correlated with stroke (HR: 0.88, 95% CI: 0.79-0.97, <i>p</i> for interaction = 0.026) and ischemic stroke (HR: 0.88, 95% CI: 0.80-0.98, <i>p</i> 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. <i>MTHFR C677T</i> gene polymorphism could potentially modify the folate-stroke relationship.