Establishing the Causal Role of Low Vitamin D in Multiple Sclerosis

确定低维生素 D 与多发性硬化症的因果关系

• 批准号: 9124580
• 负责人: Brooke Rhead
• 金额: $ 3.91万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9124580
• 关键词: Address; Affect; Autoimmune Diseases of the Nervous System; Autoimmune Process; Binding; Binding Sites; Biological; Birth; Caring; Characteristics; Data; Data Set; Demyelinating Diseases; Development; Diet; Disease; Dose; Down-Regulation; Environment; Environmental Risk Factor; Epidemiologic Studies; Etiology; Future; Gene Expression Regulation; Genes; Genetic; Genetic Risk; Genetic study; Genome; Genomic Segment; Genotype; Goals; Health; Immune; Lead; Measures; Mediating; Medical; Metabolism; Mission; Multiple Sclerosis; Myelin Sheath; National Institute of Neurological Disorders and Stroke; Neurons; Outcome; Participant; Pathogenesis; Pathway interactions; Population; Positioning Attribute; Predisposition; Prospective Studies; Proteins; Quality of life; Regulatory Pathway; Research; Risk; Risk Factors; Role; Sampling; Serum; Severities; Severity of illness; Sun Exposure; The Sun; Therapeutic; Up-Regulation; Variant; Vitamin D; Vitamin D Response Element; Vitamin D supplementation; Vitamin D3 Receptor; Work; avoidance behavior; burden of illness; case control; disability; disorder risk; evidence base; genetic risk factor; genetic variant; genome wide association study; genomic data; high risk; insight; interdisciplinary approach; lifestyle factors; link protein; nervous system disorder; programs; promoter; protective effect; public health relevance; receptor binding; response

 DESCRIPTION (provided by applicant): The objective of this project is to establish vitamin D as a causal risk factor for multiple sclerosis (MS) by investigating how variation within regions o the genome important to vitamin D influence the onset and severity of MS. MS is an immune-mediated, demyelinating disorder caused by both genetic and environmental factors. Low serum levels of vitamin D are associated with MS risk, and with increased MS activity and severity. However, a causal relationship has not been firmly established: it is unclear whether low vitamin D level is a cause of MS or a result of it, and the biological mechanism underlying the association has not been determined. The overall hypothesis of this project is that low vitamin D is truly a cause of MS, and distinct genetic variants that either lead to lower overall serum vitamin D level or that cause dysregulation of genes governed by vitamin D serve to increase MS risk or severity. This project will utilize high-quality genotype data and a rich set of clinica characteristics from ~1,500 MS cases and ~12,000 controls to address three related hypotheses. The first hypothesis is that genetic variants previously found to be associated with low serum vitamin D level in genome-wide association studies will demonstrate a causal relationship with increased MS risk or severity, independent of other known genetic and environmental risk factors. A genetic instrumental variable analysis, adjusting for known confounders and genetic ancestry, will be utilized to estimate the causal effect of low vitamin D on MS. The second hypothesis is that an association will be observed between specific genetic variants in vitamin D pathway genes or in vitamin D response elements and increased MS risk or severity. Variants in genes that affect serum vitamin D level or that are affected by vitamin D will point to the biological mechanisms through which low vitamin D is acting to influence MS pathogenesis. Pathway analyses of these vitamin D genes and MS-associated genes will be conducted using the Disease Association Protein-Protein Link Evaluator (DAPPLE). The third hypothesis is that observed effects of vitamin D variants on MS risk and severity will be replicated in independent datasets of MS cases and controls, including in non-White populations. Analyses will be pursued in other datasets of MS cases and controls to confirm significant findings. The importance in MS susceptibility and severity of both genetic and environmental factors, including low vitamin D, will be demonstrated through this research and provide new insight into the etiology of this debilitating condition, as well as other conditions where a role for vitamin D is suspected.

 描述（由适用提供）：该项目的目的是通过研究区域内的变异如何影响维生素D的基因组来影响MS的开始和严重程度，将维生素D建立为多发性硬化症（MS）的因果风险因素。 MS是由遗传和环境因素引起的一种免疫介导的脱髓鞘障碍。维生素D的低血清水平与MS风险以及MS活性和严重程度增加有关。但是，尚未建立因果关系：目前尚不清楚低维生素D水平是MS还是其结果的原因，并且尚未确定关联的生物学机制。该项目的总体假设是，低维生素D确实是MS的原因，并且具有独特的遗传变异，可导致整体血清维生素D水平降低，或者导致由维生素D控制的基因失调，从而增加MS风险或严重性。该项目将利用高质量的基因型数据和大约1,500毫秒病例和约12,000个相关假设的丰富临床特征。第一个假设是，在全基因组关联研究中，先前发现与低血清维生素D水平有关的遗传变异将证明与MS风险或严重程度增加的因果关系，与其他已知的遗传和环境风险因素无关。将利用针对已知混杂因素和遗传血统的遗传仪器变量分析来估计低维生素D对MS的因果作用。第二个假设是，在维生素D途径基因中的特定遗传变异或维生素D反应元件中，将观察到缔合，并增加MS风险或严重性。影响血清维生素D水平或受维生素D影响的基因中的变体将指向低维生素D的生物学机制来影响MS发病机理。这些维生素D基因和与MS相关基因的途径分析将使用疾病缔合蛋白 - 蛋白质链接链接评估符（DAPPLE）进行。第三个假设是，观察到的维生素D变体对MS风险和严重程度的影响将在MS病例和对照组的独立数据集中复制，包括在非白人种群中。将在MS病例和控件的其他数据集中进行分析，以确认重大发现。这项研究将证明遗传因素和环境因素（包括低维生素D）的MS易感性和严重程度的重要性，并提供对这种衰弱状况的病因的新见解，以及其他怀疑维生素D的作用。