Direct and indirect effects of obesity genes on multiple sclerosis

 描述(申请人提供)：这个项目的目标是调查肥胖基因的变异如何影响多发性硬化症(MS)的发病和严重程度。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，许多研究表明，与正常体重的人相比，儿童或青少年肥胖者患多发性硬化症的风险增加了两倍以上，尽管发生这种情况的生物学机制尚不清楚。由于MS和肥胖都是炎症性疾病，所以有可能有共同的遗传和生物途径导致肥胖并导致MS的易感性。分布在基因组中的40个基因已经被发现与肥胖相关的特征有关；然而，它们可能如何与多发性硬化症的发病或疾病严重程度有关之前还没有被研究过。该项目的总体假设是，与肥胖相关的基因变异将显示出对MS发病或严重程度的直接和间接影响。这个项目将利用高质量的基因数据，详细的体重指数病史，以及其他 来自约1,500例患者和约12,000名对照的临床特征，以解决三个相关假说。首先，与肥胖相关的基因变异将通过体重指数对多发性硬化症的发病或严重程度产生直接和间接影响。将利用基于回归的中介分析，调整已知的混杂因素和遗传血统，以测试这些影响的存在。其次，对肥胖和已建立的多发性硬化症基因的通路分析将确定可能影响多发性硬化症发病风险或严重程度的生物学途径。已确定的肥胖和多发性硬化症相关基因的路径分析将使用疾病协会蛋白质-蛋白质链接评估器(DAPPLE)进行。第三，观察到的肥胖变异对多发性硬化症发病或严重程度的影响将在多发性硬化症病例和对照的独立数据集中重复。将在多发性硬化症病例和对照的第二个数据集中进行分析，以确认重要的发现。这项研究将证明包括肥胖在内的遗传和环境因素在多发性硬化症易感性和严重性中的重要性，并为这种衰弱疾病的病因和其他与肥胖有关的疾病提供新的见解。 有嫌疑。

 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.