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Association of Serum 25-Hydroxyvitamin D With Stroke: Observational Mediation and Mendelian Randomization Study
Ming-Chieh Tsai1,2,3, Hsien-Yu Fan1,4, Hsin-Yin Hsu1,3,5
1Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10055, Taiwan.
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.
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