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
unsure
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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- Vitamin D and it’s related genes regulate the immune system – Aug 2023
- Graves' disease 2X more likely if poor Vitamin D Receptor (like many other autoimmune diseases) – May 2021
- Autoimmune disease treated by Vitamin D, Zinc (and other activators of Vitamin D Receptor) – Oct 2019
- Vitamin D Receptor is associated in over 58 autoimmune studies
- Temporary hair loss (Telogen Effluvium) is 15X more likely if poor Vitamin D Receptor – Oct 2019
- Autoimmunity problems often associated with poor Vitamin D Receptors – March 2019
- Many autoimmune diseases associated with low vitamin D or poor Vit D genes – July 2019
- Adaptive and innate immune system, vitamin D genes, and Rheumatoid Arthritis – June 2019
- Resveratrol Role in Autoimmune Disease-A Mini-Review. – Dec 2016
- Immunological effects of vitamin D and their relations to autoimmunity – March 2019
- Resveratrol improves health (Vitamin D receptor, etc.) - many studies
- Vitiligo (spotty skin coloring) is 4 X more likely if poor Vitamin D Receptor – meta-analysis July 2018
- Vitamin D Receptor and autoimmune diseases – Jan 2017
- Inflammation and immune responses to Vitamin D (perhaps need to measure active vitamin D) – July 2017
- Familial Mediterranean Fever is 3X more likely if poor Vitamin D Receptors (males) – Sept 2017
- Many autoimmune diseases associated with latitude and vitamin D receptor – March 2016
- Vitamin D Receptor role in Autoimmune Diseases and or cancers – Nov 2013
- Endometriosis treated, and perhaps prevented, by vitamin D - many studies