| Sumario: | Objective: To identify whether serum vitamin D [25(OH)D] and vitamin D receptor‐binding variants (VDR‐BVs) previously implicated in multiple sclerosis (MS) are associated with Sjögren disease (SjD) susceptibility and related clinical outcomes, with the overall goal of understanding the relationship between vitamin D and SjD pathogenesis. Methods: We constructed genetic instrumental variables (GIVs) for 25(OH)D using results from five genome‐wide association studies and established VDR‐BVs from experimental studies and then employed a two‐sample Mendelian randomization (MR) approach. We assessed the separate associations of 25(OH)D (GIV25(OH)D) and VDR binding (GIVVDR) with SjD susceptibility and related clinical outcomes in a cohort of 984 cases and 4,595 controls of European and Asian genetic ancestry. Logistic regression was used to estimate the associations for each GIV, adjusting for the first five genome‐wide principal components and sex. Results: One VDR‐BV previously found to be causally associated with MS, rs2531804, was also significantly associated with SjD (P < 0.05) in European individuals. Decreased 25(OH)D was not significantly associated with SjD overall, or when European and Asian subgroups were considered separately. Conclusion: This study is the first to investigate genetic variants implicated in previous MR studies of the vitamin D pathway in MS for a role in SjD. Although a role for decreased serum vitamin D in SjD was not supported here, results show that variation within at least one VDR causally contributes to SjD susceptibility in European individuals. Additional research is necessary to more comprehensively understand how vitamin D contributes to SjD pathogenesis across different ancestry groups.
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