Multiple sclerosis journal - experimental, translational and clinical, Volume 11, Issue 2, 1 1 2025, Pages 20552173251335625 Allele-specific vitamin D receptor binding is associated with pediatric-onset multiple sclerosis. Yilmaz D, Adams C, Horton MK, Graves JS, Francisco C, Edwards A, Quach H, Quach D, Aaen G, Lotze T, Mar S, Ness J, Wheeler Y, Gorman MP, Benson L, Weinstock-Guttman B, Waldman A, Schreiner T, Tillema JM, Chitnis T, Rose J, Casper TC, Rensel M, Waubant E, Barcellos LF, Network of Pediatric Multiple Sclerosis Centers

Background and objectives

The genetic basis of adult-onset multiple sclerosis (MS) is well-studied, but less is known about pediatric-onset MS (pedMS), comprising approximately 5% of all MS onsets. Mendelian randomization (MR) studies have demonstrated evidence for a causal association between MS and both 25-hydroxyvitamin D [25(OH)D] serum levels and genetic variation related to vitamin D receptor (VDR) binding. The objective was to identify whether VDR binding variants (VDR-BVs) previously implicated in adult-onset MS were associated with pedMS using genetic instrumental variables (GIVs).

Methods

Using previously identified VDR-BVs to construct individual GIVs with two-sample MR, we investigated associations with pedMS in 725 cases and 592 controls of European ancestry from the US Network of Pediatric MS Centers. Associations between each VDR-BV and pedMS were estimated using logistic regression adjusting for the first three genome-wide principal components. A significant interaction between a VDR-BV and 25(OH)D GIV provided evidence for a causal association unbiased by pleiotropy.

Results

One VDR-BV, rs2531804, previously associated with adult-onset MS, was also significantly associated with pedMS after multiple testing correction.

Discussion

This study is the first to use VDR-BVs from previous MR studies to demonstrate causal differences in VDR binding at a locus contributing to pedMS susceptibility.

Mult Scler J Exp Transl Clin. 2025 4;11(2):20552173251335625