Non-linear association between serum 25-hydroxyvitamin D levels and cardiovascular outcomes: Evidence from NHANES and mendelian randomization analysis.

BACKGROUND AND AIMS: The relationship between serum 25-hydroxyvitamin D (25(OH)D) and cardiovascular health is more complex than previously recognized. Observational studies link 25(OH)D deficiency to cardiovascular risk, while intervention trials show inconsistent results. This study evaluates the association between 25(OH)D levels and cardiovascular outcomes using both observational and genetic approaches, focusing on non-linear relationships and causality.

METHODS AND RESULTS: We obtained data from the National Health and Nutrition Examination Survey (NHANES) 2021-2023, including 4792 adults aged ≥18 years with complete 25(OH)D measurements and cardiovascular assessments. Analysis across 25(OH)D quartiles (≤56.7, 56.8-78.1, 78.2-103.0, >103.0 nmol/L) showed distinct patterns. In fully adjusted models, the highest quartile had significantly elevated risks for coronary heart disease (CHD) (OR = 1.97, 95 % CI: 1.34-2.89, P < 0.001) and hypertension (OR = 1.48, 95 % CI: 1.28-1.71, P < 0.001) compared to the lowest quartile. Mendelian randomization analysis provided evidence of causal relationships with CHD (β = -0.465, SE = 0.137, P = 7.08 × 10-4) and heart failure (β = -0.088, SE = 0.035, P = 0.011). Restricted cubic spline analyses revealed U-shaped associations, with optimal 25(OH)D levels (56.8-78.1 nmol/L) corresponding to lowest cardiovascular risk.

CONCLUSION: Our findings reveal non-linear relationships between 25(OH)D and cardiovascular outcomes, with both observational and genetic evidence indicating causality for certain conditions. Results suggest that the optimal 25(OH)D range for cardiovascular health may be narrower than previously thought, highlighting the importance of maintaining balanced levels through personalized supplementation strategies.