Association of Serum 25-Hydroxyvitamin D With Stroke: Observational Mediation and Mendelian Randomization Study

Abstract

Abstract Context The causal association and biological mechanism linking serum 25-hydroxyvitamin D (25(OH)D) to stroke risk lacks epidemiological evidence. Objective This study aimed to investigate the association between 25(OH)D concentration and stroke risk as well as the potential mediating factors. Design The community-based prospective community-based cohort study, the Chin-Shan Community Cardiovascular Cohort, was conducted from 1990 to December 2011, with external validation using a 2-sample Mendelian randomization (MR) study. Patients A total of 1778 participants with serum 25(OH)D data were enrolled. Methods In the Chin-Shan Community Cardiovascular Cohort observational study, the outcome was ascertained as stroke, while in the 2-sample MR study, it was defined as ischemic stroke. Causal effects were estimated using restricted cubic spline analysis, COX proportional hazard ratios, mediation analysis, and 2-sample MR. Results Over 12 years (21 598 person-years) of follow-up, 163 participants (9.17%) developed stroke. Higher 25(OH)D concentrations were associated with lower stroke risk (hazard ratio: 0.64; 95% confidence interval, 0.43-0.96) after full-model adjustments. Mediation analysis showed a significant association between 25(OH)D concentration and stroke risk mediated by hypertension in unadjusted models (mediation percentage 23.3%, P = .008) that became nonsignificant in full models (mediation percentage, 15.5%; P = .072). Two-sample MR confirmed a significant inverse association between genetically determined 25(OH)D and stroke risk (inverse variance weighted method odds ratio 0.92; 95% confidence interval: 0.85-0.99; P = .036). However, hypertension had an insignificant mediating role in the MR study. Conclusion Higher 25(OH)D levels are linked to reduced stroke risk, potentially mediated by hypertension. Prioritizing blood pressure management may improve stroke prevention in 25(OH)D-deficient patients.