Studies of HLA Region Genomics in Systemic Sclerosis and Ankylosing Spondyilitis

系统性硬化症和强直性脊柱炎 HLA 区域基因组学研究

基本信息

批准号：
7992671
负责人：
Maureen Maureen Mayes
金额：
$ 57.31万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7992671
关键词：
Alleles Ankylosing spondylitis Autoantibodies Autoimmune Diseases Candidate Disease Gene Caucasians Caucasoid Race Centromere China Chinese People Clinical DNA Data Databases Development Diffuse Diffuse Scleroderma Disease Disease Association Enrollment Ethnic group Etiology Fibrosis Gender Genes Genetic Genetic Polymorphism Genetic Variation Genomics Genotype HLA-B Antigens HLA-B27 Antigen Haplotypes Immune Lead Linkage Disequilibrium Major Histocompatibility Complex Maps Mediating Mica Mission PTPN22 gene Pathogenesis Patients Pattern Predisposition Principal Investigator RNA Polymerase III Race Resistance Resolution Resources Rheumatoid Arthritis Risk Role STAT4 gene Serological Severities Skin Spain Staging Subgroup Susceptibility Gene Systemic Lupus Erythematosus Systemic Scleroderma Type I DNA Topoisomerases Variant Work clinically relevant disorder risk falls genetic association genome wide association study human leukocyte antigen gene outcome forecast public health relevance rheumatologist

项目摘要

DESCRIPTION (provided by applicant): Systemic sclerosis (SSc) and ankylosing spondylitis (AS) are two immune-mediated diseases, the former an autoimmune disease associated with specific alleles of HLA class II DR, DQ and DP, and the latter an autoinflammatory disease associated with HLA class I alleles, most specifically HLA-B27. However, the MHC contribution to neither disease can be fully explained by associations with only these classic HLA alleles. Recent genome-wide association studies (GWAS) conducted by us have shown that the strongest disease-association loci fall within the major histocompatibility complex (MHC) in both diseases. Polymorphisms of multiple classic and non-classic HLA genes within the HLA region displayed significant associations with each of the diseases. These observations suggest that some non-classic HLA gene variants also may contribute to susceptibility to or protection from these two diseases. However, because of the extensive linkage disequilibrium (LD) between genes within the HLA region, some of observed disease associations may be due to LD. Alternatively, multiple true MHC associations may additively heighten or lower disease risk. To circumvent this problem, we propose herein to examine these candidate genes identified from the GWAS with deep sequencing in three distinct ethnic groups. Sequencing candidate genes will provide the highest resolution for viewing genetic polymorphisms that can be used to construct comprehensive haplotype combinations, as well as to identify rare alleles. Subsequently, identified haplotypes and rare alleles will be examined in different ethnic groups for confirmation in an effort to locate causative gene variants to the diseases. The overall long-term objective of this proposal is to define the roles of specific HLA-region gene variations in susceptibility to or protection from SSc and AS, as well as in association with specific clinical presentations, disease subgroups and/ or severity. Information obtained from these studies will ultimately lead to understanding of disease pathogenesis and development of target specific therapies in SSc and AS. This proposal will fulfill the mission of the FOA to study HLA region genomics in immune-mediated diseases. PUBLIC HEALTH RELEVANCE (provided by applicant): The greatest risk for immune-mediated diseases such as systemic sclerosis (SSc) and ankylosing spondylitis (AS) have been associated with specific gene variants within the major histocompatibility complex. Our proposal aims to define these variants that contribute to greater or lower susceptibility to SSc and AS, which will ultimately lead to understanding of disease pathogenesis and development of target specific therapies.

描述（由申请人提供）：全身性硬化症（SSC）和强直性脊柱炎（AS）是两种免疫介导的疾病，前者是与HLA II类DR，DQ和DP的特定等位基因相关的自身免疫性疾病，而后者是与HLA ILLA ILELELES相关的自身炎症性疾病，而HLA ILLA ILELELES是HLA ILELELES，大多数HLA-B27。但是，仅与这些经典HLA等位基因的关联可以充分解释MHC对这两个疾病的贡献。美国进行的最新基因组关联研究（GWAS）表明，两种疾病中最强的疾病缔合基因座属于主要的组织相容性复合物（MHC）。 HLA区域内多种经典和非经典HLA基因的多态性与每种疾病都有显着关联。这些观察结果表明，某些非经典HLA基因变体也可能有助于对这两种疾病的敏感性或保护。但是，由于HLA区域内基因之间存在广泛的连锁不平衡（LD），因此某些观察到的疾病关联可能是由于LD造成的。另外，多个真正的MHC关联可能会增加或降低疾病的风险。为了解决这个问题，我们在本文中提议检查从GWAS鉴定出的这些候选基因，并在三个不同的族裔中进行深度测序。测序候选基因将提供最高的分辨率，以查看可用于构建全面的单倍型组合以及鉴定稀有等位基因的遗传多态性。随后，将在不同种族中检查确定的单倍型和稀有等位基因，以确认以定位疾病的病因基因变异。该提案的总体长期目标是定义特定的HLA区域基因变异在对SSC的易感性或保护以及与特定临床表现，疾病亚组和/或严重程度相关联的特定HLA-区域基因变异的作用。从这些研究中获得的信息最终将导致对疾病发病机理的理解和SSC和AS中特定特定疗法的发展。该提案将履行FOA在免疫介导疾病中研究HLA地区基因组学的使命。公共卫生相关性（由申请人提供）：免疫介导的疾病（例如全身性硬化症（SSC）和强直性脊柱炎（AS））的最大风险与主要组织相容性复合物中的特定基因变异体有关。我们的建议旨在定义这些变体对SSC的敏感性更大或更低，这最终将导致对疾病发病机理和靶标特异性疗法的发育的理解。