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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：
8677681
负责人：
Maureen Maureen Mayes
金额：
$ 51.36万
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 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8677681
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 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 deep sequencing disorder risk falls genetic association genetic variant genome wide association study human leukocyte antigen gene outcome forecast rare variant 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.

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将最终导致对疾病发病机制的理解和SSc和AS靶向特异性治疗的发展。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。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Profiling of hla-B alleles for association studies with ankylosing spondylitis in the chinese population.

DOI：
10.2174/1874312920130628001
发表时间：
2013
期刊：
The open rheumatology journal
影响因子：
0
作者：
Yi L;Wang J;Guo X;Espitia MG;Chen E;Assassi S;Jin L;Zou H;Reveille JD;Zhou X
通讯作者：
Zhou X

Identification of an Association of TNFAIP3 Polymorphisms With Matrix Metalloproteinase Expression in Fibroblasts in an Integrative Study of Systemic Sclerosis-Associated Genetic and Environmental Factors.