Format

Send to

Choose Destination
Hum Mol Genet. 2017 Jun 1;26(11):2164-2176. doi: 10.1093/hmg/ddx092.

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

Author information

1
MRC Functional Genomics Unit.
2
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK.
3
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
4
Real-World Evidence, Evidera, London W6 8DL, UK.
5
MRC Human Genetics Unit, The Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
6
Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7BN, UK.
7
CGAT, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
8
MRC-PHE Centre for Environment and Health, Department of Epidemiology & Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, UK.

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.

PMID:
28335003
PMCID:
PMC5886188
DOI:
10.1093/hmg/ddx092
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center