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• W2949205861 endingPage "2176" @default.
• W2949205861 startingPage "2164" @default.
• W2949205861 abstract "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 < 0.1) and substantially (>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." @default.
• W2949205861 created "2019-06-27" @default.
• W2949205861 creator A5006998673 @default.
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• W2949205861 creator A5057792696 @default.
• W2949205861 creator A5070882955 @default.
• W2949205861 creator A5075816415 @default.
• W2949205861 date "2017-03-09" @default.
• W2949205861 modified "2023-09-23" @default.
• W2949205861 title "Identification of genetic variants affecting vitamin D receptor binding and associations with autoimmune disease" @default.
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• W2949205861 doi "https://doi.org/10.1093/hmg/ddx092" @default.
• W2949205861 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5886188" @default.
• W2949205861 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/28335003" @default.
• W2949205861 hasPublicationYear "2017" @default.
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