Establishing the Role of Genetic Variation in Vitamin D Regulated Gene Expression in Multiple Sclerosis Pathogenesis
Approved Research ID: 69668
Approval date: April 13th 2021
Multiple sclerosis (MS) is an immune-mediated disease that can cause significant physical and neurological disability, and its cause is unknown. MS occurs more often in regions farther from the equator, leading to the hypothesis that vitamin D exposure has a protective effect on MS risk. Recent studies have demonstrated strong evidence for a causal role of low serum vitamin D in MS; however, the exact nature of the relationship between vitamin D and MS is unknown. It is well established that vitamin D signaling in the body operates through the nuclear vitamin D receptor (VDR), which is involved in the expression of gene products. VDRs recognize and bind to specific places in the human DNA sequence, leading to activation or suppression of a target gene. Previous research has found that DNA sequence variation occurs within these VDR binding sites in the human genome, and can have an impact on this important biological process. These VDR binding sites have been identified in genomic regions already known to be associated with MS, which suggests regulation of specific genes mediated by vitamin D could affect MS risk. These VDR binding sites also exist in many other areas of the genome. No formal investigation of genetic variation within individual VDR binding sites in MS cases and controls has been conducted, and VDR binding sites across the genome, in general, are strong candidates to investigate for a relationship to MS.
The overall goal of this project is to estimate the effect of genetic variation within VDR binding sites on the risk of developing MS. We hypothesize that this genetic variation is associated with MS susceptibility, and further, that the effect of this genetic variation on MS is modulated by bioavailability of vitamin D, which can also be characterized using genetic information derived from the human genome. Results obtained from the work in this proposal will help us understand the mechanisms through which vitamin D affects MS; our findings will have implications for understanding what causes other chronic diseases that are associated with vitamin D, including several cancers, Alzheimer's disease and other autoimmune/inflammatory conditions. This project is expected to begin in January 2021 and continue until January 2023.