Vitamin D genetic risk scores in multiple sclerosis

Background: Low serum 25(OH)D₃ (vD) is an environmental risk factor for multiple sclerosis (MS). Lower vD levels during early disease may be associated with long-term disability. Determinants of serum vD levels in healthy individuals include supplementation behaviour and genetic factors. These determinants have been less well studied in people with MS (pwMS).

Methods: We developed a vD-weighted genetic risk score (GRS) and validated this in 373,357 UK Biobank participants without MS. We measured serum 25(OH)D₃ and genotyped six vD-associated SNPs (rs12785878, rs10741657, rs17216707, rs10745742, rs8018720, rs2282679) in a cohort of pwMS (n = 315) with age and geographically matched controls (n = 232). We then assessed predictors of serum vD concentration in this cohort.

Results: The GRS was strongly associated with vD status in the Biobank cohort (p < 2 × 10^-16). vD supplementation, having MS, lower BMI, increased age and supplementation dose were associated with higher vD levels (false discovery rate, FDR < 5%). In multivariable models adjusting for supplementation, BMI, age, sex, and MS status, the GRS was strongly associated with vD level (p = 0.004), but not in those who supplemented (p = 0.47).

Conclusions: Our findings suggest that vD supplementation is the major determinant of vD level in pwMS, with genetic determinants playing a far smaller role.