Serum Vitamin D Levels do not Affect Susceptibility to EBV Infection. A Mendelian Randomization Study.

Abstract Introduction: Epstein-Barr virus (EBV) infection and low serum 25-hydroxyvitamin D (25OHD) levels are strongly associated with multiple sclerosis (MS). We investigated whether genetically proxied serum vitamin D levels are causally linked to EBV infection, assessed by serology and detectable EBV DNA, using Mendelian randomisation (MR). Methods: We conducted two-sample cis-MR using genetic instruments associated with serum 25OHD concentrations, restricted to variants near genes implicated in vitamin D metabolism. Outcomes included EBV seropositivity, antibody responses to four EBV antigens, detectable EBV DNA in blood and saliva, and MS case status as a positive control. Results: Genetically proxied vitamin D levels had no clear effect on EBV seropositivity (odds ratio per standard deviation (SD) increase in rank-based inverse-normal transformation (RINT) 25OHD: 1.76, 95% confidence interval [CI] 0.83-3.73) or antibody responses to EBV antigens. No significant associations were observed with detectable EBV DNA in blood (beta 0.02, 95% CI −0.004 to 0.04) or saliva (beta 0.02, 95% CI −0.23 to 0.26). In contrast, genetically proxied vitamin D levels were associated with reduced MS risk (odds ratio per SD increase in RINT 25OHD 0.67, 95% CI 0.54-0.84). Discussion: We found no clear evidence that genetically proxied vitamin D levels causally influence EBV serological responses or detectable EBV DNA in blood or saliva. The protective association with MS supports previous genetic evidence. These findings suggest that vitamin D and EBV may influence MS risk through distinct pathways, although effects specific to early-life vitamin D exposure remain possible.