Vitamin D and vitamin D receptor polymorphisms modify cardiovascular outcomes in asthma: a prospective cohort study based on the UK Biobank

The association between vitamin D (VD) status and cardiovascular disease (CVD) risk in patients with asthma remains unclear, and the role of vitamin D receptor (VDR) polymorphisms in this context is not well established. This study aimed to investigate the associations of vitamin D status and VDR polymorphisms with incident CVD risk in patients with asthma. We included 30,534 asthmatic and 251,249 non-asthmatic participants from the UK Biobank. The relationship between serum 25(OH)D levels and CVD risk in asthma was assessed using multivariable-adjusted restricted cubic spline and Cox proportional hazards models. The analyses for effect modification (by VDR polymorphisms) and mediation (by predefined factors) were conducted using Cox models with interaction terms and a bootstrap-based mediation approach (1,000 resamples), respectively. Additionally, CVD risks were compared across 25(OH)D categories between asthmatic and non-asthmatic participants. A significant L-shaped association was observed between serum 25(OH)D levels and incident CVD risk in patients with asthma (P for nonlinearity = 0.002), with an inflection point at approximately 50 nmol/L. After multivariable adjustment, asthmatic patients with 25(OH)D levels ≥ 75 nmol/L had a significantly lower CVD risk than those with levels < 25 nmol/L (HR: 0.83; 95% CI: 0.76–0.91; P < 0.001). Among asthmatic patients with severe vitamin D deficiency, the T allele of BsmI (rs1544410) and the G allele of TaqI (rs731236) were associated with a significant attenuation of the protective effect of vitamin D against CVD, whereas the A allele of ApaI (rs7975232) significantly enhanced this protective association. Mediation analysis indicated that body mass index, log-transformed C-reactive protein, and glycated hemoglobin accounted for 35.50%, 20.66%, and 9.88% of the total protective effect of vitamin D, respectively. Furthermore, compared with the non-asthmatic population, asthmatic individuals had a higher CVD risk across all 25(OH)D categories, but the magnitude of this excess risk demonstrated a decreasing trend with increasing vitamin D levels. Lower vitamin D status is nonlinearly associated with an elevated CVD risk in asthma patients. VDR polymorphisms modify this protective effect in cases of severe vitamin D deficiency. These findings underscore the importance of maintaining adequate 25(OH)D levels for CVD prevention in asthma.