Novel Strategies to Identify GxE Contributions to MS Pathogenesis

描述（由申请人提供）：多发性硬化（MS）是一种中枢神经系统的复杂和异质性炎症性疾病，其特征在于髓鞘丢失、不同程度的轴突病理和进行性神经功能障碍。许多基因的综合作用，在生命的特定时期内作用的环境暴露，以及它们在MS中的相互作用，得到了我们自己和其他人的工作的有力支持。染色体6p 21上的主要组织相容性复合体（MHC）内的HLA II类基因的参与是公认的。MS易感性的非MHC决定因素的鉴定虽然在进展，但远未完成。与其他复杂疾病相似，全基因组关联研究（GWAS）已经开始揭示MS的多基因病因。然而，迄今为止，通过几个大型GWAS鉴定的变体只能解释MS遗传性的一小部分。拟议的研究描述了GWAS时代后的关键步骤，以进一步了解我们目前对MS发病机制的了解。首先，我们将利用下一代DNA序列数据，高通量基因分型和最先进的生物信息学方法，充分表征通过最近GWAS建立的30多个MS基因中的罕见，不太常见和常见的变异及其对MS发展和疾病表达的贡献（目标1）。接下来，我们还将全面研究一些重要的生命过程暴露，包括产前、围产期、儿童、青少年和成人时间段、GxE相互作用和MS风险（目标2）。最后，我们将研究一个新建立的临床孤立综合征（CIS）/早期MS病例和匹配对照组的全基因组DNA甲基化谱，以确定免疫细胞特异性表观遗传对MS发展的影响（目的3）。我们将利用特殊的MS病例对照资源，这些资源嵌套在北方加州Kaiser Permanente的大型、基于人群的成员中，以及通过国际多发性硬化症遗传学联盟为本项目收集的DNA、遗传和临床数据;将使用一套统计分析方法研究10，000多名白色/欧洲血统的个体。在相关环境暴露的背景下，对最重要的MS基因和致病变体进行流行病学研究的结果将为新的功能研究提供信息，并有可能支持开发更有效的预防、诊断和治疗方法。 公共卫生相关性：遗传和环境影响的完整鉴定以及它们如何独立地和共同地促进MS的发展和特定疾病特征的表达将在理解疾病病因学中发挥重要作用，并且将极大地有助于疾病预防策略和靶向和更有效的疗法的开发。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a complex and heterogeneous inflammatory disorder of the central nervous system characterized by myelin loss, varying degrees of axonal pathology, and progressive neurological dysfunction. The combined effect of many genes, environmental exposures acting during defined periods of life, and their interactions in MS is strongly supported by our own work and others. The involvement of HLA class II genes within the major histocompatibility complex (MHC) on chromosome 6p21 is well-established. The identification of non-MHC determinants of MS susceptibility, while progressing, is far from complete. Similar to other complex diseases, genome-wide association studies (GWAS) have begun to unravel the polygenic etiology of MS. However, variants identified through several large GWAS, to date, explain only a very small proportion of MS heritability. The proposed study describes critical post-GWAS era steps to further our current understanding of MS pathogenesis. First, we will utilize next-generation DNA sequence data, high-throughput genotyping and state-of-the-art bioinformatics methods to fully characterize rare, less frequent and common variants within more than 30 MS genes established through recent GWAS and their contribution to the development of MS and disease expression (Aim 1). Next, we will also comprehensively investigate a number of important life-course exposures including prenatal, perinatal, childhood, adolescent and adult time periods, GxE interactions and risk of MS (Aim 2). Finally, we will study genome-wide DNA methylation profiles in a newly established cohort of clinically isolated syndrome (CIS)/early MS cases and matched controls to identify immune cell specific epigenetic influences on the development of MS (Aim 3). We will utilize extraordinary MS case-control resources nested within the large, population-based membership of Northern California Kaiser Permanente, as well as DNA, genetic and clinical data assembled for this project through the International Multiple Sclerosis Genetics Consortium; more than 10,000 individuals of White/European ancestry will be studied using a suite of statistical methods of analysis. Results from proposed epidemiologic studies of the most important MS genes and causal variants in the context of relevant environmental exposures will inform new functional studies, and have potential to support the development of more effective approaches for prevention, diagnosis and treatment. PUBLIC HEALTH RELEVANCE: The complete identification of genetic and environmental influences and how they contribute independently and jointly to the development of MS and expression of particular disease characteristics would play a major role in understanding disease etiology, and would contribute greatly to disease prevention strategies and development of targeted and more effective therapies.