The Identification of Risk Factors for the Complex MS Phenotype

描述（由申请人提供）：多发性硬化症（MS）是一种复杂的、异质性的中枢神经系统（CNS）炎症性疾病，其特征是髓磷脂丢失、神经胶质瘤、不同程度的轴突病理和进行性神经功能障碍。在美国和欧洲国家，多发性硬化症是成年早期和中期获得性神经功能障碍的最常见原因，全世界有超过100万人受到影响。这项建议的目的是确定遗传因素和遗传和非遗传风险因素之间复杂的相互作用，易患MS和相关表型。我们首次在多发性硬化症中描述了一种强大而新颖的方法，该方法基于强大的初步数据来追求明确的假设，这些数据对于进一步了解疾病发病机制至关重要。该提案的主要重点将是确定复杂的风险因素(A)易患自身免疫易感性MS表型，(2)通过存在或不存在已建立的疾病相关HLA-DRB1*15基因型和其他环境暴露来区分MS亚组，以及(c)应用新颖而强大的分析工具来识别复杂的关系，包括相互作用。可以预测疾病状态或相关表型的大量潜在危险因素之间的联系。我们将研究一个由2400人组成的大型、特征明确的基于人群的MS病例对照数据集。我们将使用完善的严格的MS病例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，图表审查和综合访谈，以确定明确的MS诊断和重要的表型指定。将进行超过55万个信息丰富的单核苷酸多态性的最先进的高通量基因分型。完全阐明潜在疾病风险和异质性MS表型的遗传和非遗传影响将在理解疾病生物学方面发挥重要作用，并将对疾病预防和开发更有针对性和更有效的治疗方法做出重大贡献。项目的叙述

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.