Identification of genetic variants affecting vitamin D receptor binding and associations with 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 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.
MRC Functional Genomics Unit.|Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
Giuseppe
G
Gallone
MRC Functional Genomics Unit.|Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK.
Wilfried
W
Haerty
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK.
Giulio
G
Disanto
Real-World Evidence, Evidera, London W6 8DL, UK.
Sreeram V
SV
Ramagopalan
MRC Functional Genomics Unit.|Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK.|MRC Human Genetics Unit, The Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
Chris P
CP
Ponting
Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7BN, UK.|CGAT, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.|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.
Antonio J
AJ
Berlanga-Taylor
D001327:Autoimmune Diseases / Q000235:genetics*; D002117:Calcitriol / Q000378:metabolism; D002460:Cell Line; D014644:Genetic Variation / Q000235:genetics; D016678:Genome; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D014807:Vitamin D / Q000378:metabolism
D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; D014157:Transcription Factors; C579457:VDR protein, human; D014807:Vitamin D; D002117:Calcitriol