MHC variation at high resolution in multiple sclerosis

多发性硬化症中 MHC 高分辨率变异

基本信息

批准号：
10133162
负责人：
JILL Allison HOLLENBACH
金额：
$ 63.29万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10133162
关键词：
6p21 Address Affect African African American Age Alleles American Autoimmune Autoimmune Diseases Automobile Driving Binding Binding Sites Bioinformatics Central Nervous System Diseases Characteristics Chromosomes Clinical Data Code Communicable Diseases Coupled Custom DNA Data Data Analyses Data Set Databases Development Disease Disease Progression Disease susceptibility European Future Gene Cluster Gene Expression Gene Expression Regulation Genes Genetic Genetic Epistasis Genetic Polymorphism Genomic DNA Goals HLA Antigens Health Heterogeneity Histocompatibility Antigens Histocompatibility Antigens Class II Human Immune Immune response Immune system Immunity Inflammatory Intercistronic Region Laboratories Libraries Link Linkage Disequilibrium MHC Class I Genes Magnetic Resonance Imaging Major Histocompatibility Complex Major Histocompatibility Complex Gene Malignant Neoplasms Maps Methodology Methods Methylation MicroRNAs Modeling Molecular Multiple Sclerosis Nerve Degeneration Neurologic Oligonucleotide Probes Onset of illness Pathogenesis Pathway Analysis Pharmaceutical Preparations Phenotype Physiology Population Predisposition Process Quantitative Trait Loci RNA Splicing Reaction Regulatory Element Research Research Design Research Personnel Resolution Risk Role Sampling Sequence Analysis Severity of illness Signal Transduction Site Structure System Technology Tissues Translating Untranslated RNA Variant analysis pipeline bioinformatics tool causal variant chronic inflammatory disease cohort deep sequencing design disability disease phenotype epigenomics experience gene interaction genetic information genetic signature genetic variant genome editing genome wide association study genome-wide insight multidisciplinary multiple sclerosis patient next generation sequencing novel preclinical study response risk variant sex transcriptome sequencing young adult

项目摘要

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.

我们建议以高分辨率研究多个主要组织相容性复合体 (MHC) 位点硬化症（MS），一种中枢神经系统慢性炎症性疾病，也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) 基因簇位于染色体 6p21 上，并解释了高达 10% 的潜在风险遗传变异。该区域包含约 165 个基因，其中约一半在免疫系统中发挥关键作用。其中包括人类白细胞抗原 (HLA) 基因，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。尽管持续的研究努力关于 MS 中的 HLA 区域，需要进一步研究以生成统一且可测试的机制模型与疾病发病机制有关。通过研究大型且特征鲜明的群体，我们的目标是揭示免疫多态性对风险和进展的贡献的重要方面。我们的实验方法涉及 5 Mb MHC 的完整测序，产生高深度覆盖外显子和内含子以及基因间片段，从而识别与该基因相关的所有可能的变异表型，并区分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 个 MS 病例和 2,000 个对照进行 MHC 测序，以及非洲血统，用于序列和结构变异的综合分析。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来允许具有监管潜力的 MHC 变体的鉴定。最后，在具体目标 3 中，我们将采用基因组编辑技术建立一个强大的细胞平台，能够有效筛选已识别的候选变体，优先考虑基因表达和基因间相互作用的调节。完整描述信息丰富的多祖先 MS 数据集中的 MHC 变异，再加上最先进的生物信息学和假设驱动的分子方法有望对遗传基础产生新的见解疾病易感性。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A splice acceptor variant in HLA-DRA affects the conformation and cellular localization of the class II DR alpha-chain.

HLA-DRA 中的剪接受体变体影响 II 类 DR α 链的构象和细胞定位。

DOI：
发表时间：
2021
期刊：
影响因子：
6.4
作者：
Didonna, Alessandro;Damotte, Vincent;Shams, Hengameh;Matsunaga, Atsuko;Caillier, Stacy J;Dandekar, Ravi;Misra, Maneesh K;Mofrad, Mohammad R K;Oksenberg, Jorge R;Hollenbach, Jill A
通讯作者：
Hollenbach, Jill A

Specific hypomethylation programs underpin B cell activation in early multiple sclerosis.

特定的低甲基化程序支持早期多发性硬化症中 B 细胞的激活。

DOI：
发表时间：
2021-12-21
期刊：
影响因子：
11.1
作者：
Ma, Qin;Caillier, Stacy J;Muzic, Shaun;University of California San Francisco MS;Wilson, Michael R;Henry, Roland G;Cree, Bruce A C;Hauser, Stephen L;Didonna, Alessandro;Oksenberg, Jorge R
通讯作者：
Oksenberg, Jorge R