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Vitamin D Receptor and autoimmune diseases – Jan 2017

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

Initally in Preprint Server bioRxiv doi: https://doi.org/10.1101/080143
Now published in Human Molecular Genetics doi: https://doi.org/10.1093/hmg/ddx092
Giuseppe Gallone, Wilfried Haerty, Giulio Disanto, Sreeram Ramagopalan, Chris P Ponting, Antonio J Berlanga-Taylor

This may be a chart of VDR activation vs 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 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.
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19 Items in both categories VDR and Autoimmune

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