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

• 批准号: 8111111
• 负责人: Maureen Maureen Mayes
• 金额: $ 55.71万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 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/8111111
• 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

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（申请人提供）：系统性硬化症（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，后者是与HLA I类等位基因相关的自身炎症性疾病，最具体的是HLA-B27。然而，MHC对这两种疾病的贡献都不能完全解释为仅与这些经典HLA等位基因相关。我们最近进行的全基因组关联研究（GWAS）表明，在这两种疾病中，最强的疾病关联位点位于主要组织相容性复合体（MHC）内。HLA区域内多个经典和非经典HLA基因的多态性与每种疾病都有显著相关性。这些观察结果表明，一些非经典的HLA基因变异也可能有助于对这两种疾病的易感性或保护。然而，由于HLA区域内基因之间存在广泛的连锁不平衡（LD），一些观察到的疾病相关性可能是由于LD。或者，多个真正的MHC协会可能会增加或降低疾病的风险。为了解决这个问题，我们在此提出在三个不同的种族群体中用深度测序来检查从GWAS中鉴定的这些候选基因。测序候选基因将提供最高的分辨率，用于查看遗传多态性，可用于构建全面的单倍型组合，以及识别罕见的等位基因。随后，将在不同种族群体中检查已鉴定的单倍型和罕见等位基因，以确定疾病的致病基因变异。 本提案的总体长期目标是确定特定HLA区域基因变异在SSc和AS易感性或保护中的作用，以及与特定临床表现、疾病亚组和/或严重程度的相关性。从这些研究中获得的信息最终将有助于了解SSc和AS的疾病发病机制和靶向特异性疗法的开发。 该提案将完成FOA的使命，研究免疫介导疾病的HLA区域基因组学。 公共卫生相关性（由申请人提供）：免疫介导疾病（如系统性硬化症（SSc）和强直性脊柱炎（AS））的最大风险与主要组织相容性复合体内的特定基因变异相关。我们的提案旨在定义这些变异，这些变异有助于增加或降低对SSc和AS的易感性，这将最终导致对疾病发病机制的理解和靶向特异性治疗的发展。