The Identification of Risk Factors for the Complex MS Phenotype

描述（由申请人提供）：多发性硬化（MS）是一种中枢神经系统（CNS）的复杂和异质性炎症性疾病，其特征为髓鞘丢失、神经胶质增生、不同程度的轴突病理和进行性神经功能障碍。MS是美国和欧洲国家在成年早期和中期出现的获得性神经功能障碍的最常见原因，它影响了全球100多万人。该提案的目标是确定遗传因素以及遗传和非遗传风险因素之间的复杂相互作用，这些因素易患MS和相关表型。我们在MS中首次描述了一种强大而新颖的方法，该方法基于对进一步了解疾病发病机制至关重要的强有力的初步数据来追求定义明确的假设。该提案的主要重点将是识别复杂的风险因素，这些因素（a）易患自身免疫易感性MS表型，和（2）区分MS亚组，所述MS亚组由存在或不存在已确立的疾病相关HLA-DRB 1 *15基因型和其他环境暴露来定义，和（c）应用新的和强大的分析工具来识别复杂的关系，包括相互作用，大量的潜在危险因素之间的联系，可以预测疾病状态或相关表型。我们将研究一个大型的，充分表征的基于人群的MS病例对照数据集，包括2,400个个体。我们将使用完善的MS病例严格确定标准和一套复杂的工具，包括电子数据库调查，直接联系医生，图表审查和全面访谈，以确定明确的MS诊断和本研究的重要表型命名。将对超过550，000个信息性单核苷酸多态性进行最先进的高通量基因分型。对疾病风险和异质性MS表型潜在的遗传和非遗传影响的完全阐明将在理解疾病生物学方面发挥重要作用，并将显著有助于疾病预防和靶向和更有效治疗的开发。项目叙述 多发性硬化症（MS）代表了医疗保健系统的身体，情感，社会和财政负担，并且像其他自身免疫性疾病一样，是一个重要的公共卫生问题，导致生产力下降和生活质量下降。诊断后15年，不到20%的患者没有功能限制; 50-60%的患者需要步行辅助，至少70%的患者无法进行正常的日常活动，75%的患者失业。遗传和非遗传因素对MS的影响的完全阐明将在理解疾病生物学方面发挥重要作用，并将显著有助于疾病预防和开发靶向和更有效的治疗方法。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a complex and heterogeneous inflammatory disorder of the central nervous system (CNS) characterized by myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. MS is the most common cause of acquired neurological disability in the U.S. and European countries arising during early and mid-adulthood, and it affects more than one million people worldwide. The goal of this proposal is to identify genetic factors and complex interactions between genetic and non- genetic risk factors that predispose to MS and related phenotypes. We describe for the very first time in MS, a powerful and novel approach to pursue well-defined hypotheses based on strong preliminary data that are critical to furthering our understanding of disease pathogenesis. A major focus of this proposal will be the identification of complex risk factors that (a) predispose to the autoimmune prone MS phenotype, and (2) distinguish between MS subgroups defined by the presence or absence of the well-established disease associated HLA-DRB1*15 genotype and other environmental exposures, and (c) the application of novel and powerful analytical tools to identify complex relationships, including interactions, between large numbers of potential risk factors that can predict disease status or related phenotypes. We will study a large, well characterized population-based MS case- control data set comprised of 2,400 individuals. We will use well-established strict ascertainment criteria for MS cases and a suite of sophisticated tools including electronic database surveying, direct physician contact, chart review and comprehensive interviews to determine definite MS diagnoses and important phenotypic designations for this study. State of the art high-throughput genotyping of more than 550,000 informative single nucleotide polymorphisms will be performed. The complete elucidation of genetic and non- genetic influences underlying disease risk and heterogeneous MS phenotypes would clearly play a major role in understanding disease biology and would contribute significantly to disease prevention and the development of targeted and more effective therapeutics. PROJECT NARRATIVE Multiple sclerosis (MS) represents a physical, emotional, social and fiscal burden to the health care system and like other autoimmune disorders is a significant public health concern resulting in lost productivity and decreased quality of life. Fifteen years after diagnosis, less than 20% of patients have no functional limitations; 50-60% require ambulating assistance, at least 70% are unable to perform normal daily activities, and 75% are unemployed. The complete elucidation of genetic and non-genetic influences underlying MS would clearly play a major role in understanding disease biology and would contribute significantly to disease prevention and the development of targeted and more effective therapeutics.