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

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.

SUBMITTER: Gallone G

PROVIDER: S-EPMC5886188 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Gallone Giuseppe G Haerty Wilfried W Disanto Giulio G Ramagopalan Sreeram V SV Ponting Chris P CP Berlanga-Taylor Antonio J AJ

Human molecular genetics 20170601 11

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 modifi ...[more]

PMID: 28335003

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Project description:Estrogen receptor (ER) activity is critical for the development and progression of the majority of breast cancers. It is known that ER is differentially bound to DNA leading to transcriptomic and phenotypic changes in different breast cancer models. We investigated whether single nucleotide variants (SNVs) in ER binding sites (regSNVs) contribute to ER action through changes in the ER cistrome, thereby affecting disease progression. Here we developed a computational pipeline to identify SNVs in ER binding sites using chromatin immunoprecipitation sequencing (ChIP-seq) data from ER+ breast cancer models.ER ChIP-seq data were downloaded from the Gene Expression Omnibus (GEO). GATK pipeline was used to identify SNVs and the MACS algorithm was employed to call DNA-binding sites. Determination of the potential effect of a given SNV in a binding site was inferred using reimplementation of the is-rSNP algorithm. The Cancer Genome Atlas (TCGA) data were integrated to correlate the regSNVs and gene expression in breast tumors. ChIP and luciferase assays were used to assess the allele-specific binding.Analysis of ER ChIP-seq data from MCF7 cells identified an intronic SNV in the IGF1R gene, rs62022087, predicted to increase ER binding. Functional studies confirmed that ER binds preferentially to rs62022087 versus the wild-type allele. By integrating 43 ER ChIP-seq datasets, multi-omics, and clinical data, we identified 17 regSNVs associated with altered expression of adjacent genes in ER+ disease. Of these, the top candidate was in the promoter of the GSTM1 gene and was associated with higher expression of GSTM1 in breast tumors. Survival analysis of patients with ER+ tumors revealed that higher expression of GSTM1, responsible for detoxifying carcinogens, was correlated with better outcome.In conclusion, we have developed a computational approach that is capable of identifying putative regSNVs in ER ChIP-binding sites. These non-coding variants could potentially regulate target genes and may contribute to clinical prognosis in breast cancer.

Dataset Information

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

Publications

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

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