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

确定遗传变异在维生素 D 调节基因表达中在 MS 发病机制和严重程度中的作用

基本信息

批准号：
10356902
负责人：
Cameron Adams
金额：
$ 2.57万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356902
关键词：
25-hydroxyvitamin D Affect Affinity Autoimmune Diseases Binding Binding Sites Biological Biological Availability California ChIP-seq Childhood Clinical DNA Data Data Set Development Disease Environment Environmental Exposure Environmental Risk Factor Ethnic Origin Fellowship Frequencies Gene Expression Gene Expression Regulation Genes Genetic Genetic Risk Genetic Variation Genome Genomic Segment Genotype Goals Health Human Genome Immune Investigation Ligands Linkage Disequilibrium Machine Learning Measures Mediating Mendelian randomization Meta-Analysis Mission Molecular Multiple Sclerosis Myelin Sheath National Institute of Neurological Disorders and Stroke Neurons Nuclear Outcome Pathogenesis Predisposition Prevalence Publishing Quality of life Race Regulation Regulatory Pathway Reporting Research Risk Risk Factors Role Serum Severities Severity of illness Signal Transduction Study Subject Sun Exposure Testing United States Variant Vitamin D Vitamin D supplementation Vitamin D3 Receptor Work burden of illness case control cohort disability epidemiology study evidence base genetic risk factor genome wide association study genomic data improved individual variation interdisciplinary approach lymphoblastoid cell line multiple datasets nervous system disorder pediatric multiple sclerosis programs protective effect receptor binding risk variant transcription factor whole genome

项目摘要

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.

项目概要多发性硬化症 (MS) 是一种免疫介导的疾病，会破坏周围的保护性髓鞘神经细胞，其原因尚不清楚。远离赤道的地区 MS 患病率较高，导致该假设认为，阳光照射以及随之而来的维生素 D 摄入对多发性硬化症风险具有保护作用。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，分子该关联的机制尚不清楚。众所周知，25(OH)D 信号传导的运作通过核维生素 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 结合位点内标记 SNP (VDR-BV) 的遗传变异可以改变结合亲和力。这些 VDR-BV 富含与 MS 以及其他几种自身免疫性疾病相关的基因组区域疾病，这表明维生素 D 介导的特定基因的调节可能会影响多发性硬化症的风险和严重程度。尚未报道对 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 相关的遗传变异的有力候选者。总体目标该 F31 应用程序旨在评估 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 易感性和严重程度相关，而且这种影响 MS 的遗传变异受维生素 D 的生物利用度调节。我们的方法将使用以下数据集大约 10,000 例临床明确的多发性硬化症病例和 35,000 例对照频率与年龄和年龄相匹配具有全基因组基因型、人口统计、临床和环境暴露数据的种族/民族，并将： 1) 估计已确定的 MS 风险位点附近的 VDR-BV 与 MS 风险和严重程度之间的关联； 2）估计人类基因组中的 VDR-BV 与 MS 风险和严重程度之间的关联；和 3) 在多发性硬化症病例和对照的独立数据集中复制研究结果，并将跨组复制的关联结合起来所有数据集均通过荟萃分析。先前通过 ChIP-seq 分析在淋巴母细胞中鉴定了 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。分析将包括遗传工具变量作为 25(OH)D 生物利用度的测量，以测试 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 VDR 结合亲和力的遗传变异部分解释了这一点，确定 MS 的遗传风险因素与维生素 D 相关，并确定参与发育的新基因和调控途径多发性硬化症。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。介导的神经障碍。