Vitamin D metabolites, genetic variants, and risk of cardiovascular diseases among individuals with newly diagnosed type 2 diabetes: a prospective study.

Evidence regarding individual vitamin D metabolites and cardiovascular diseases (CVD) among individuals with type 2 diabetes (T2D) remains limited. This study aimed to investigate the prospective associations of plasma vitamin D metabolites with incident CVD among individuals with newly diagnosed T2D. This study included 1122 participants with newly diagnosed T2D from the Dongfeng-Tongji Cohort study in China. Plasma vitamin D metabolites were quantified using liquid chromatography-tandem mass spectrometry. Sixty single-nucleotide polymorphisms (SNPs) in genes involved in vitamin D metabolic pathways were genotyped. Incidence of CVD was ascertained via electronic health records. During 9284 person-years of follow-up, we documented 520 incident CVD cases. Higher concentrations of plasma 24,25(OH)2D3 and 25(OH)D3 were associated with a lower risk of incident CVD; comparing the highest with the lowest quartiles, multivariable-adjusted HRs (95% CIs) were 0.71 (0.55, 0.92) and 0.74 (0.58, 0.96), respectively. After false discovery rate (FDR) correction for multiple comparisons, the inverse association with 24,25(OH)2D3 remained statistically significant (PFDR = 0.012), whereas the association with 25(OH)D3 was marginally significant (PFDR = 0.064). No significant associations were observed for 3-epi-25(OH)D3 (0.81 [0.63-1.05]) or vitamin D3 (0.97 [0.76-1.24]). Restricted cubic spline analysis suggested a potential nonlinear association between 25(OH)D2 and CVD risk (P for overall = 0.007; P for nonlinearity = 0.002). In exploratory genetic analyses, nominal associations were observed for variants in CYP2R1 and CYP3A4, as well as for their potential interactions with vitamin D metabolites, although none remained significant after FDR correction. These findings suggest that vitamin D metabolites may have distinct associations with incident CVD among individuals with T2D, highlighting the importance of distinguishing individual vitamin D metabolites in CVD risk assessment. These findings warrant further validation in independent populations.