MHC variation at high resolution in multiple sclerosis

我们建议以高分辨率研究多个组织中的主要组织相容性复合体（MHC）基因座， 硬化症（MS），一种中枢神经系统的慢性炎症性疾病，是非- 年轻人的创伤性神经功能障碍。超过200个位点与易感性密切相关。 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 在染色体6p 21，并解释高达10%的遗传变异潜在的风险。该地区包含 大约165个基因，其中大约一半在免疫系统中起关键作用。其中包括人类白细胞 抗原（HLA）基因，已与100多个感染性，自身免疫性和 炎性疾病表型以及药物反应和癌症。尽管持续的研究努力 在多发性硬化症的HLA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 与疾病的发病机制有关。通过检查大型和特征良好的队列，我们的目标是揭示 免疫多态性对风险和进展的重要方面。我们 实验方法涉及5 Mb MHC的完全测序，产生高深度覆盖， 外显子和内含子以及基因间片段，从而鉴定与基因突变相关的所有可能的变体。 表型，并区分在非编码区不同的其他相同的经典HLA等位基因。在 具体目标1：我们将对代表欧洲的2,000例MS病例和2,000例对照进行MHC测序， 非洲祖先的序列和结构变化的综合分析。具体目标2 将实施系统级途径分析管道，利用大型开放获取数据库， 鉴定具有调节潜力的MHC变体。最后，在具体目标3中，我们将采用基因组 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 候选变体，优先考虑基因表达和基因-基因相互作用的调节。完整描述 MHC变异的信息，多祖先MS数据集，加上最先进的生物信息学和 假设驱动的分子方法有望产生新的见解的遗传基础， 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.