Causal Association of Genetically Determined Circulating Vitamin D Metabolites and Calcium with Multiple Sclerosis in Participants of European Descent

Background Vitamin D is an important regulator of calcium. Mendelian randomization (MR) studies exclusively focused on the circulating total 25-hydroxyvitamin D (25(OH)D) as a biomarker of vitamin D status, and have found the causal association between 25(OH)D and the risk of multiple sclerosis (MS). However, it currently remains unclear about the causal association of the 25(OH)D subtypes including 25(OH)D3 and C3-epi-25(OH)D3, as well as calcium with the risk of MS. Methods We performed a two-sample MR study to evaluate the causal association of circulating total 25(OH)D, 25(OH)D3, C3-epi-25(OH)D3, and calcium with the risk of MS using large-scale genome-wide association studies (GWAS) datasets from total 25(OH)D ( n = 417,580), 25(OH)D3 ( n = 40,562), C3-epi-25(OH)D3 ( n = 40,562), calcium ( n = 305,349), and MS (14,802 MS and 26,703 controls). We selected five MR methods including inverse-variance weighted (IVW), simple median, weighted median, MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier), and contamination mixture method. Results IVW showed that the genetically increased circulating 25(OH)D level (OR = 0.81, 95% CI: 0.70–0.94, P = 4.00E-03), circulating 25(OH)D3 level (OR = 0.85, 95% CI: 0.76–0.95, P = 5.00E-03), and circulating C3-epi-25(OH)D3 level (OR = 0.85, 95% CI: 0.74–0.98, P = 2.30E-02) were causally associated with reduced risk of MS. However, IVW showed no causal association between circulating calcium level and the risk of MS with OR = 2.85, 95% CI: 0.42–19.53, P = 2.85E-01. Conclusions Our current findings together with evidence from other MR studies support the use of vitamin D but not calcium supplementation for the prevention of MS.