Genetic and non-genetic risk factors in MS

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易患MS和调节表型表达和/或进展的遗传和非遗传因素。我们描述了第一次在MS，一个强大的方法来追求强有力的和明确的假设，以进一步了解疾病的发病机制。我们将调查和完善几个有前途的候选基因的作用，暴露于香烟烟雾和潜在的基因-环境相互作用，以及与女性生殖史相关的因素在MS易感性和疾病调制使用一个大的，充分表征的人口为基础的病例对照数据集，包括3000个人。我们将使用完善的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。将利用最先进的高通量基因分型方法和新颖全面的分析方法。对疾病风险和异质性MS表型的遗传和非遗传影响的完整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 and non-genetic factors that predispose to MS and modulate phenotypic expression and/or progression. We describe for the first time in MS, a powerful approach to pursue strong and well-defined hypotheses critical to furthering our understanding of disease pathogenesis. We will investigate and refine the role of several promising candidate genes, the exposure to cigarette smoke and potential gene-environment interactions, and factors related to female reproductive history in MS susceptibility and disease modulation using a large, well characterized population-based case-control data set comprised of 3000 individuals. We will use well established strict ascertainment criteria 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 methodologies and novel and comprehensive analytical approaches will be utilized. The complete elucidation of genetic and nongenetic 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.