Non-linear Association Between Serum 25-hydroxyvitamin D Levels and Cardiovascular Outcomes: Evidence from NHANES and Mendelian Randomization Analysis - May 2015
Nutrition, Metabolism and Cardiovascular Diseases https://doi.org/10.1016/j.numecd.2025.104155 entire PDF is behind a paywall
Highlights
- Our study addresses a crucial question in nutritional epidemiology: the causal relationship between Serum 25-hydroxyvitamin D status and cardiovascular outcomes. Using data from 4,792 participants in the NHANES database (2021-2023), combined with Mendelian randomization analysis, we provide comprehensive evidence for pathway-specific effects of 25(OH)D on cardiovascular health. Our key findings include:
- Differential associations across cardiovascular outcomes, with strong observational evidence showing increased cardiovascular disease prevalence across 25(OH)D quartiles (coronary heart disease: 3.5% to 7.8%, ARD=4.3%, P<0.001).
- Robust causal evidence from Mendelian randomization analysis for coronary heart disease (β=-0.465, P=7.08×10-4) and heart failure (β=-0.088, P=0.011), while finding no significant causal effect on hypertension.
- Important implications for personalized 25(OH)D supplementation strategies in cardiovascular disease prevention, particularly relevant to your journal's focus on nutrition-related interventions in cardiovascular health.
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 4,792 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.