Association of Vitamin C Supplementation and Genetic Susceptibility With Multiple Sclerosis Risk: A Prospective Population-Based Cohort Study

Abstract

Introduction: Multiple sclerosis (MS) is a chronic immune-mediated neurological disorder of the central nervous system and a leading cause of neurological disability[1]. Vitamin C, due to its antioxidant and neuroprotective properties, [2-4] has been hypothesized to reduce MS risk, but epidemiological evidence remains limited and inconsistent [5,6]. Furthermore, it is unclear whether its association varies according to an individual’s genetic susceptibility to MS.

Aim: this study aimed to evaluate the association between vitamin C supplementation and MS risk, and to assess whether this relationship is modified by the MS polygenic risk score (MS-PRS) for MS.

Methods: To this aim we conducted a prospective cohort study using UK Biobank data [7], including 486,908 adults aged 37-70 years free of neurological disease at baseline. Vitamin C supplementation was self-reported at recruitment. Incident MS cases were identified during a median follow-up of 13.5 years. Propensity score-based Inverse Probability of Treatment Weighting (IPTW) [8] was used to balance a wide range of demographic, lifestyle, dietary, health-related, and supplement-use confounders. Weighted Cox proportional hazards models were used to estimate hazard ratios (HRs). Furthermore, we examined whether the association differed according to genetic susceptibility to MS, measured using MS-PRS.

Results: During follow-up, 452 participants were diagnosed with MS. Vitamin C supplementation was reported by 8.8% of participants and was associated with a 49% lower risk of MS (HR=0.51, [95% CI: 0.32; 0.82], p=0.004). The estimate was robust across multiple sensitivity analyses, including a negative control outcome analysis. The association was stronger among individuals with higher MS-PRS (HR=0.31, [95% CI: 0.17; 0.55], p<0.001), whereas no significant association was observed among those with lower MS-PRS. No interaction was observed by sex or age, although estimates suggested a potentially stronger association in younger individuals.

Conclusions: In this large prospective cohort, vitamin C supplementation was associated with a lower risk of incident MS, particularly among individuals with higher genetic susceptibility. Although residual confounding cannot be excluded, the consistency of the association in this large prospective cohort and its biological plausibility support further investigation of vitamin C as a candidate modifiable factor for MS prevention.