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

项目摘要 多发性硬化症(MS)是一种免疫介导的疾病，破坏周围保护性的髓鞘 神经细胞，其原因不明。MS患病率在距离赤道较远的地区较高，导致 这一假设认为，阳光照射以及随后的维生素D暴露对患多发性硬化症的风险具有保护作用。 最近利用孟德尔随机化(MR)分析的研究已经证明了因果关系的有力证据 低水平血清25-羟基维生素D(25(OH)D)在MS发病机制中的作用 这种联系背后的机制尚不清楚。众所周知，25(OH)D信令是工作的 通过核维生素D受体(VDR)，一种配体调节的转录因子。VDR识别特定的 DNA中的结合部位，导致目标基因的激活或抑制。此前的研究发现， 这些VDR结合位点内标签SNPs(VDR-BV)的遗传变异可以改变结合亲和力。这些 VDR-BV在与多发性硬化症和其他几种自身免疫相关的基因组区域中富含 疾病，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。 目前还没有关于多发性硬化症患者和对照个体VDR-BV基因变异的正式调查报告 和VDR-BV是研究与MS相关的遗传变异的有力候选者。 此F31应用程序用于评估VDR-BV对MS风险和严重程度的影响。我们假设 VDR-BV的遗传变异与MS的易感性和严重程度有关，而且，这种影响 多发性硬化症的遗传变异是由维生素D的生物可利用性调节的。我们的方法将使用 大约10,000名临床确诊的多发性硬化症患者和35,000名对照的频率在年龄和 种族/民族，包括全基因组基因型别、人口统计、临床和环境暴露数据，并将： 1)估计已建立的多发性硬化症风险位点附近的VDR-BV与多发性硬化症风险和严重程度的关系；2) 评估人类基因组中VDR-BV与多发性硬化症风险和严重程度之间的关联；以及3) 复制MS病例和对照的独立数据集中的发现，并将复制的关联组合到 通过荟萃分析获得所有数据集。先前通过芯片序列分析在淋巴母细胞中发现了VDR-BV。 我们将使用机器学习来确定AIM 2的候选VDR-BV的优先级。分析将结合 用于检测VDR-BV之间相互作用的25(OH)D生物利用度的遗传仪器变量 25(OH)D生物利用度。提议的AIMS的结果将决定MS Gwas的调查结果 部分原因是VDR结合亲和力的遗传变异，确定MS的遗传危险因素 与维生素D相关，并确定参与维生素D发育的新基因和调控途径 最终，这项工作的目标是了解维生素D影响这种免疫力的机制。 介导性神经紊乱。

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.