Imperial College London
Alternate

Dr Antonio J Berlanga-Taylor

Faculty of Medicine, School of Public Health

Honorary Senior Research Fellow
 
 
 
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Contact

 

a.berlanga

 
 
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Location

 

47 Praed StreetSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@unpublished{Gallone:2017:10.1101/080143,
author = {Gallone, G and Haerty, W and Disanto, G and Ramagopalan, S and Ponting, C and Berlanga-Taylor, A},
doi = {10.1101/080143},
publisher = {Oxford University Press (OUP)},
title = {Identification of genetic variants affecting vitamin D receptor binding and associations with autoimmune disease},
url = {http://dx.doi.org/10.1101/080143},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - UNPB
AB  - 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.
AU  - Gallone,G
AU  - Haerty,W
AU  - Disanto,G
AU  - Ramagopalan,S
AU  - Ponting,C
AU  - Berlanga-Taylor,A
DO  - 10.1101/080143
PB  - Oxford University Press (OUP)
PY  - 2017///
TI  - Identification of genetic variants affecting vitamin D receptor binding and associations with autoimmune disease
UR  - http://dx.doi.org/10.1101/080143
ER  -
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