MHC variation at high resolution in multiple sclerosis

我们建议在高分辨率下研究多发性骨髓瘤的主要组织相容性复合体(MHC)基因座。 硬化症(MS)，一种慢性中枢神经系统炎症性疾病，常见的非 年轻人的创伤性神经功能障碍。有200多个基因座与易感性密切相关。 主要关联信号全基因组映射到主要组织相容性复合体(MHC)基因簇 位于染色体6p21上，解释了高达10%的潜在风险的遗传变异。此区域包含 大约165个基因，大约一半在免疫系统中起着关键作用。其中包括人类白细胞。 抗原(HLA)基因，已与100多种传染性、自身免疫性和 炎症性疾病表型，以及药物反应和癌症。尽管有持续的研究努力 关于多发性硬化症的人类白细胞抗原区域，需要进一步的研究来产生统一的和可测试的机制模型 与疾病发病机制有关。通过研究大量和特征良好的队列，我们的目标是揭示 免疫多态对风险和进展的贡献的重要方面。我们的 实验方法涉及5Mb MHC的完整测序，产生高度深度的覆盖 外显子和内含子以及基因间片段，从而确定所有可能的与 表型，以及区分在非编码区不同的其他相同的经典HLA等位基因。在……里面 具体目标1我们将对代表欧洲的2,000例多发性硬化症病例和2,000例对照的MHC进行测序，以及 非洲祖先，对序列和结构变异进行全面分析。在具体目标2中，我们 将实施系统级路径分析管道，利用大型开放访问数据库 具有调控潜力的MHC变异体的鉴定。最后，在特定的目标3中，我们将使用基因组 编辑技术，以建立一个强大的蜂窝平台，能够有效地筛选已识别的 候选变异体，优先调控基因表达和基因-基因相互作用。完整描述 在信息丰富的多祖先MS数据集中的MHC变异，结合最先进的生物信息学和 假说驱动的分子方法有望为人类疾病的遗传基础提供新的见解 疾病易感性。

We proposed to study at high resolution the Major Histocompatibility Complex (MHC) locus in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system and common cause of non- traumatic neurological disability in young adults. Over 200 loci have been firmly associated with susceptibility. The main association signal genome-wide maps to the major histocompatibility complex (MHC) gene cluster in chromosome 6p21, and explains up to 10% of the genetic variance underlying risk. This region contains ~165 genes, about half having pivotal roles in the immune system. These include the human leukocyte antigen (HLA) genes, which have been associated with more than 100 infectious, autoimmune and inflammatory disease phenotypes, as well as drug reactions and cancers. Despite a sustained research effort on the HLA region in MS, further studies are needed to generate unifying and testable mechanistic models connected to disease pathogenesis. By examining large and well-characterized cohorts, we aim to reveal important aspects of the contribution of immune polymorphism to both, risk and progression. Our experimental approach involves complete sequencing of the 5 Mb MHC, generating high depth coverage of exonic and intronic as well intergenic segments, thus identifying all possible variants associated with the phenotypes, and distinguishing otherwise identical classical HLA alleles that differ in noncoding regions. In Specific Aim 1 we will sequence the MHC in 2,000 MS cases and 2,000 controls representing European, and African ancestries for a comprehensive analysis of sequence and structure variation. In Specific Aim 2 we will implement a systems-level pathway analysis pipeline, leveraging large open access databases to allow the identification of MHC variants with regulatory potential. Finally, in Specific Aim 3 we will employ genomic editing technologies to setup a robust cellular platform with the capability to efficiently screen the identified candidate variants, prioritizing on regulation of gene expression and gene-gene interactions. Full description of MHC variation in informative, poly-ancestral MS datasets, coupled with state-of the art-bioinformatics and hypothesis driven molecular approaches promises to yield novel insights into the genetic underpinnings of disease susceptibility.