Citations 1
Allele-specific vitamin D receptor binding is associated with pediatric-onset multiple sclerosis
Yilmaz, Defne , Adams, Cameron , Francisco, Carla , Rutatangwa, Alice , Quach, Hong , Quach, Diana , Aaen, Gregory , Lotze, Timothy , Mar, Soe , Ness, Jayne , Wheeler, Yolanda , Gorman, Mark , Schreiner, Teri , Tillema, Jan-Mendelt , Rose, John , Casper, T. Charles , Barcellos, Lisa F. , Edwards, Alice Rutatangwa , Benson, Leslie A , Weinstock‐Guttman, Bianca , Schreiner, Teri , Rensel, Mary R. , Horton, Mary , Graves, Jennifer , Benson, Leslie , Waldman, Amy , Tillema, Jan‐Mendelt , Chitnis, Tanuja , Waubant, Emmanuelle L.
Multiple Sclerosis Journal – Experimental, Translational and Clinical | May 27, 2025 | Volume: 11 | Issue: 2 | Pages: No page available
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.