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.

Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti‐Inflammatory

“…(136) Additionally, in both cell lines and human T cells, when cells were cultured in the presence of low serum 25D, it was shown that there was decreased binding of the VDR to multiple gene variants commonly identified in GWASs to predispose to autoimmune disease. (137) The above studies highlight the complex nature of disease susceptibility, but strongly suggest a role for vitamin D in limiting the pathogenicity of T-cell-mediated autoimmune diseases.…”

The Role of Vitamin D in the Pathogenesis of Inflammatory Bowel Disease

“…As proof of concept for the role of vitamin D in the pathogenesis of IBD, the vitamin D receptor gene maps to a region of chromosome 12, which is also linked to IBD [36]. Moreover, polymorphisms of the vitamin D receptor have been linked to IBD phenotypes, pointing toward a relationship between altered affinity of vitamin D to its receptor and IBD [49][50][51][52][53][54][55].…”

“…The VDR gene is located in a chromosome 12 region that has been linked to IBD by genome screening techniques. Genetic variation might alter the binding affinity of the vitamin D VDR and it was associated with immune and inflammatory disease, including IBD [36].…”

An Inter-Method Reliability Study Comparing Interview Information on Sunlight, Tanning Beds, Food, and Supplement Exposures with Serum 25-Hydroxy Vitamin D Levels

“…However, unlike other nutrients, it is also synthesized in the skin in response to exposure to ultraviolet B (UVB) radiation (e.g., from sunlight). While vitamin D sufficiency is closely tied with bone 3 health(1), it has also been linked to a number of other disease states from cancer (2) to autoimmune disorders (3) to dementia (4). Along with direct measurement of circulating 25-hydroxy vitamin D (25(OH)D) levels, surveys and questionnaires are often used to estimate vitamin D related exposures such as sunlight exposure, tanning bed use, dietary intake, and supplement use.…”