Novel Strategies to Identify GxE Contributions to MS Pathogenesis

描述(申请人提供)：多发性硬化症(MS)是一种复杂的异质性中枢神经系统炎症性疾病，以髓鞘丢失、不同程度的轴突病理和进行性神经功能障碍为特征。我们自己和其他人的工作有力地支持了许多基因、在特定生命阶段作用的环境暴露以及它们在多发性硬化症中的相互作用的综合作用。人类白细胞抗原II类基因与染色体6p21上的主要组织相容性复合体(MHC)有关。对MS易感性的非MHC决定因素的鉴定虽然取得了进展，但远未完成。与其他复杂疾病类似，全基因组关联研究(GWAS)已经开始揭开MS的多基因病因，然而，到目前为止，通过几个大型GWAS发现的变异只能解释很小一部分MS的遗传性。这项拟议的研究描述了后GWAS时代的关键步骤，以加深我们目前对MS发病机制的理解。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，充分表征通过最近的GWAS建立的30多个MS基因中的罕见、不太频繁和常见的变异及其对MS的发展和疾病表达的贡献(目标1)。接下来，我们还将全面调查一些重要的生命过程暴露，包括产前、围产期、儿童期、青春期和成年期，GxE相互作用和多发性硬化症的风险(目标2)。最后，我们将研究一组新建立的临床隔离综合征(CIS)/早期MS病例和匹配对照的全基因组DNA甲基化图谱，以确定免疫细胞特异性表观遗传学对MS发展的影响(目标3)。我们将利用北加州Kaiser Permanente庞大的基于人群的成员中嵌套的非凡的MS病例对照资源，以及通过国际多发性硬化症遗传学联合会为该项目收集的DNA、遗传和临床数据；将使用一套统计分析方法对10,000多名白人/欧洲血统的个人进行研究。在相关环境暴露的背景下，对最重要的MS基因和因果变异的拟议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：完全确定遗传和环境影响以及它们如何独立和共同促进多发性硬化症的发展和特定疾病特征的表现，将在理解疾病病因方面发挥重要作用，并将极大地有助于疾病预防战略和开发有针对性的更有效的治疗方法。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a complex and heterogeneous inflammatory disorder of the central nervous system 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.