Association of serum 25-hydroxyvitamin D with stroke: Observational mediation and Mendelian Randomization Study.

Context: The causal association and biological mechanism linking serum 25-hydroxyvitamin 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 two-sample Mendelian randomization (MR) study.
Patients: A total of 1,778 participants with serum 25-hydroxyvitamin D data were enrolled.
Methods: In the CCCC observational study, the outcome was ascertained as stroke, while in the two-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 two-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=0.008) that became non-significant in full models (mediation percentage, 15.5%; p=0.072). Two-sample MR confirmed a significant inverse association between genetically determined 25(OH)D and stroke risk (IVW OR: 0.92; 95% CI: 0.85-0.99; p=0.036). However, hypertension had an insignificant mediating role in the Mendelian randomization study.
Conclusions: 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.
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