Direct and indirect effects of obesity genes on multiple sclerosis

肥胖基因对多发性硬化症的直接和间接影响

• 批准号: 8984235
• 负责人: Milena Anne Gianfrancesco
• 金额: $ 3.69万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984235
• 关键词: Address; Adolescent; Adult; Alzheimer' s Disease; Autoimmune Diseases of the Nervous System; Autoimmune Process; Biological; Birth; Body mass index; California; Caring; Characteristics; Childhood; Clinical; Data; Data Set; Dementia; Demyelinating Diseases; Disease; Education; Elderly; Environment; Environmental Risk Factor; Etiology; Fatty acid glycerol esters; Future; Genes; Genetic; Genetic study; Genome; Genotype; Health; Immune; Impaired cognition; Individual; Inflammatory; Intervention; Life Cycle Stages; Life Style; Literature; Malignant Neoplasms; Measurement; Measures; Mediating; Mediation; Medical; Methodology; Multiple Sclerosis; Neurologic; Obesity; Observational Study; Onset of illness; Outcome; Participant; Pathogenesis; Pathway Analysis; Pathway interactions; Patient Self-Report; Positioning Attribute; Predisposition; Proteins; Quality of life; Recording of previous events; Research; Risk; Risk Factors; Role; Severities; Severity of illness; Socioeconomic Status; Testing; Therapeutic; Time; Variant; Weight; base; brain volume; case control; disability; disorder risk; genetic variant; insight; link protein; middle age; nervous system disorder; novel; programs; public health relevance; risk variant; socioeconomics; trait

 DESCRIPTION (provided by applicant): The objective of this project is to investigate how variation within obesity genes may influence the onset and severity of multiple sclerosis (MS). MS is an immune-mediated, demyelinating disorder believed to be caused by both genetic and environmental factors. Recently, individuals with childhood or adolescent obesity have demonstrated greater than a twofold increased risk of MS compared to those at a normal weight in numerous studies, though the biological mechanism through which this occurs is unknown. It is plausible that there are common genetic and biologic pathways that contribute to obesity and result in susceptibility of MS, as both MS and obesity are characterized as inflammatory diseases. Forty genes dispersed throughout the genome have been found to be associated with obesity-related traits; however, how they may relate to MS onset or disease severity has not been previously investigated. The overall hypothesis of this project is that genetic variants associated with obesity will demonstrate both direct and indirect effects on MS onset or severity. This project will utilize high-quality genotype data, detailed body mass index histories, and other clinical characteristics from ~1,500 cases and ~12,000 controls to address three related hypotheses. First, genetic variants associated with obesity will demonstrate both direct and indirect effects via body mass index on MS onset or severity. A regression-based mediation analysis, adjusting for known confounders and genetic ancestry, will be utilized to test for the presence of these effects. Second, pathway analysis of obesity and established MS genes will identify biological pathways that may influence risk of MS onset or severity. Pathway analyses of established obesity and MS associated genes will be conducted using the Disease Association Protein-Protein Link Evaluator (DAPPLE). Third, observed effects of obesity variants on MS onset or severity will be replicated in an independent dataset of MS cases and controls. Analyses will be pursued in a second dataset of MS cases and controls to confirm significant findings. The importance in MS susceptibility and severity of both genetic and environmental factors, including obesity, will be demonstrated through this research and provide new insight into the etiology of this debilitating condition and others where a role for obesity is suspected.

 描述（由适用提供）：该项目的目的是研究肥胖基因内部的变异可能如何影响多发性硬化症（MS）的发作和严重程度。 MS是一种免疫介导的脱髓鞘疾病，被认为是由遗传和环境因素引起的。最近，与许多研究相比，患有童年或青春期或青春期肥胖症的个体已显示出高于正常体重的人的两倍高于MS的风险，尽管发生这种情况的生物学机制尚不清楚。合理的是，有一些常见的遗传和生物学途径导致肥胖症并导致MS的敏感性，因为MS和肥胖症都以炎症性疾病为特征。已发现分散在整个基因组中的40个基因与肥胖相关的特征有关。但是，以前尚未研究它们与MS发作或疾病严重程度有关的方式。该项目的总体假设是，与肥胖相关的遗传变异将表现出对MS发作或严重程度的直接和间接影响。该项目将利用高质量的基因型数据，详细的体重指数历史以及其他 约有1,500例病例和约12,000例对照的临床特征，以解决三个相关假设。首先，与肥胖相关的遗传变异将通过体重指数对MS发作或严重程度表现出直接和间接影响。基于回归的中介分析调整了已知的混杂因素和遗传血统，将用于测试这些影响的存在。其次，肥胖和已建立的MS基因的途径分析将确定可能影响MS发作或严重程度的风险的生物学途径。将使用疾病关联蛋白蛋白链接评估符（Dapple）进行既定肥胖和相关基因的途径分析。第三，观察到的肥胖变体对MS发作或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。分析将在第二个MS病例和控件数据集中进行，以确认重大发现。这项研究将证明遗传和环境因素（包括肥胖）的MS易感性和严重性的重要性，并提供对这种衰弱状况的病因的新见解，而其他人的肥胖作用是肥胖的作用 怀疑。