Establishing the Role of Genetic Variation in Vitamin D Regulated Gene Expression in MS Pathogenesis and Severity

项目摘要 多发性硬化（MS）是一种免疫介导的疾病， 神经细胞，其原因尚不清楚。MS患病率在远离赤道的地区更高，导致 假设阳光照射，因此维生素D暴露，对MS风险有保护作用。 最近利用孟德尔随机化（MR）分析的研究表明， 低血清25-羟基维生素D（25（OH）D）水平在MS发病机制中的作用;然而， 这种关联的潜在机制尚不清楚。众所周知，25（OH）D信号传导 通过核维生素D受体（VDR），一种配体调节的转录因子。VDR识别特定 DNA中的结合位点，导致靶基因的激活或抑制。先前的研究发现， 这些VDR结合位点内的标记SNP（VDR-BV）的遗传变异可以改变结合亲和力。这些 VDR-BV富集在与MS相关的基因组区域，以及与其他几种自身免疫性疾病相关的基因组区域。 这表明由维生素D介导的特定基因的调节可能会影响MS的风险和严重程度。 尚未报告MS病例和对照中个体VDR-BV遗传变异的正式调查 和VDR-BV是研究与MS相关的遗传变异的强有力的候选者。 本F31应用旨在评估VDR-BV对MS风险和严重度的影响。我们假设 VDR-BV中的遗传变异与MS易感性和严重性相关，并且进一步地，这种遗传变异的影响 MS的遗传变异受维生素D的生物利用度调节。我们的方法将使用一个数据集， 大约10，000例临床确诊的MS病例和35，000例对照， 人种/种族与全基因组基因型、人口统计学、临床和环境暴露数据，并将： 1)估计已确定的MS风险基因座附近的VDR-BV与MS风险和严重程度之间的关联; 2） 估计人类基因组中VDR-BV与MS风险和严重程度之间的关联;以及3） 在MS病例和对照的独立数据集中复制发现，并将联合收割机之间的复制关联合并 所有数据集通过荟萃分析。先前通过ChIP-seq分析在淋巴母细胞瘤中鉴定了VDR-BV 细胞系，我们将使用机器学习来优先考虑目标2的候选VDR-BV。分析将纳入 作为25（OH）D生物利用度指标的遗传工具变量，用于检测VDR-BV之间的相互作用 和25（OH）D生物利用度。拟议目标的结果将决定MS GWAS的发现是否 部分解释为VDR结合亲和力的遗传变异，确定MS的遗传风险因素 与维生素D有关，并确定参与维生素D发育的新基因和调控途径。 女士最终，这项工作的目标是了解维生素D影响这种免疫的机制- 介导的神经系统疾病。

Project Summary Multiple sclerosis (MS) is an immune-mediated disease that destroys the protective myelin sheath surrounding nerve cells, and its cause is unknown. MS prevalence is higher in regions farther from the equator, leading to the hypothesis that sun exposure, and consequently vitamin D exposure, has a protective effect on MS risk. Recent studies utilizing Mendelian randomization (MR) analysis have demonstrated strong evidence for a causal role of low serum 25-hydroxyvitamin D (25(OH)D) levels in MS pathogenesis; however, the molecular mechanisms underlying the association are unknown. It is well established that 25(OH)D signaling operates through the nuclear vitamin D receptor (VDR), a ligand-regulated transcription factor. VDRs recognize specific binding sites in DNA, leading to activation or suppression of a target gene. Previous research has found that genetic variation of tagging SNPs (VDR-BVs) within these VDR binding sites, can alter binding affinity. These VDR-BVs are enriched in genomic regions associated with MS, as well as with several other autoimmune diseases, which suggests regulation of specific genes mediated by vitamin D could affect MS risk and severity. No formal investigation of genetic variation of individual VDR-BVs in MS cases and controls has been reported and VDR-BVs are strong candidates to investigate for genetic variation relevant to MS. The overall objective of this F31 application is to estimate the effect of VDR-BVs on MS risk and severity. We hypothesize that genetic variation in VDR-BVs is associated with MS susceptibility and severity, and further, that the effect of this genetic variation on MS is modulated by bioavailability of vitamin D. Our approach will use a dataset of approximately 10,000 clinically definite MS cases and 35,000 controls frequency matched on age and race/ethnicity with whole genome genotypes, demographic, clinical, and environmental exposure data and will: 1) Estimate the association between VDR-BVs near established MS risk loci and MS risk and severity; 2) Estimate the association between VDR-BVs across the human genome and MS risk and severity; and 3) Replicate findings in independent datasets of MS cases and controls and combine replicated associations across all datasets via meta-analysis. VDR-BVs were previously identified through ChIP-seq analysis in Lymphoblastoid Cell Lines and we will use machine learning to prioritize candidate VDR-BVs for Aim 2. Analyses will incorporate a genetic instrumental variable as measure of 25(OH)D bioavailability to test for interaction between VDR-BVs and 25(OH)D bioavailability. Results from the proposed aims will determine whether MS GWAS findings are partially explained by genetic variation in VDR binding affinity, identify genetic risk factors for MS related to vitamin D, and identify new genes and regulatory pathways involved in the development of MS. Ultimately, the goal of this work understand the mechanisms by which vitamin D affects this immune- mediated neurological disorder.