Identification of genetic variants affecting vitamin D receptor binding and associations with autoimmune disease

Large numbers of statistically significant associations between sentinel SNPs and case-control status have been replicated by genome-wide association studies. Nevertheless, few underlying molecular mechanisms of complex disease are currently known. We investigated whether variation in binding of a transcription factor, the vitamin D receptor (VDR), whose activating ligand vitamin D has been proposed as a modifiable factor in multiple disorders, could explain any of these associations. VDR modifies gene expression by binding DNA as a heterodimer with the Retinoid X receptor (RXR). We identified 43,332 genetic variants significantly associated with altered VDR binding affinity (VDR-BVs) using a high-resolution (ChIP-exo) genome-wide analysis of 27 HapMap lymphoblastoid cell lines. VDR-BVs are enriched in consensus RXR::VDR binding motifs, yet most fell outside of these motifs, implying that genetic variation often affects the binding affinity only indirectly. Finally, we compared 341 VDR-BVs replicating by position in multiple individuals against background sets of variants lying within VDR-binding regions that had been matched in allele frequency and were independent with respect to linkage disequilibrium. In this stringent test, these replicated VDR-BVs were significantly (q 2-fold) enriched in genomic intervals associated with autoimmune and other diseases, including inflammatory bowel disease, Crohn’s disease and rheumatoid arthritis. The approach’s validity is underscored by RXR::VDR motif sequence being predictive of binding strength and being evolutionarily constrained. Our findings are consistent with altered RXR::VDR binding contributing to immunity-related diseases. Replicated VDR-BVs associated with these disorders could represent causal disease risk alleles whose effect may be modifiable by vitamin D levels.

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Author Gallone, Giuseppe
Last Updated November 20, 2019, 16:43 (UTC)
Created August 1, 2019, 10:30 (UTC)
Article Host Type repository
Article Is Open Access true
Article License Type cc-by
Article Version Type publishedVersion
Citation Report https://scite.ai/reports/10.1093/hmg/ddx092
DOI 10.1093/hmg/ddx092
Date Last Updated 2019-07-21T20:18:44.504852
Evidence oa repository (via OAI-PMH title and first author match)
Funder code(s) Multiple Sclerosis Society (915/09); Research Councils UK (); Medical Research Council (MC_UU_12008/1, MC_UU_12021/1, MC_EX_G1000902); Wellcome Trust and Genzyme (); Council for Science and Technology (CONACyT) Mexico (211990)
Journal Is Open Access false
Open Access Status green
PDF URL https://academic.oup.com/hmg/article-pdf/26/11/2164/24340411/ddx092.pdf
Publisher URL https://academic.oup.com/hmg/article/26/11/2164/3064529