Genetic and non-genetic risk factors in MS

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。本提案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来追求强有力的和明确的假设，这对进一步了解疾病的发病机制至关重要。我们将研究和完善几个有希望的候选基因的作用，暴露于香烟烟雾和潜在的基因与环境的相互作用，以及与女性生殖史相关的因素在MS易感性和疾病调节中使用一个由3000人组成的大型、特征明确的基于人群的病例对照数据集。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诊断和重要的表型指定。国家的最先进的高通量基因分型方法和新的和全面的分析方法将被利用。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，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更有针对性和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.