Genetic and non-genetic risk factors in MS

描述(申请人提供)：多发性硬化症(MS)是一种复杂和异质性的中枢神经系统(CNS)炎症性疾病，以髓鞘丢失、胶质增生、不同程度的轴突病理和进行性神经功能障碍为特征。多发性硬化症是美国和欧洲国家后天神经功能障碍的最常见原因，出现在成年早期和中期，全球有100多万人受到影响。这项建议的目标是确定易患多发性硬化症的遗传和非遗传因素，并调节表型表达和/或进展。我们首次在多发性硬化症中描述了一种强有力的方法，以寻求强有力的和明确的假设，这对加深我们对疾病发病机制的理解至关重要。我们将使用一个由3000人组成的基于人群的大型病例对照数据集，调查和提炼几个有希望的候选基因的作用，吸烟暴露和潜在的基因-环境相互作用，以及与女性生殖史相关的因素在MS易感性和疾病调节中的作用。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、直接医生接触、病历回顾和全面访谈，以确定明确的MS诊断和重要的表型指定。将利用最先进的高通量基因分型方法和新颖而全面的分析方法。彻底阐明遗传和非遗传因素对疾病风险的潜在影响以及多发性硬化的异质性表型显然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有针对性的更有效的治疗方法做出重大贡献。

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.