HLA CLASS III GENES AND CR1 IN RHEUMATIC DISEASES

风湿性疾病中的 HLA III 类基因和 CR1

• 批准号: 2083714
• 负责人: CHACK Y YU
• 金额: $ 19.04万
• 依托单位: CHILDREN'S HOSPITAL (COLUMBUS)
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2083714
• 关键词: SDS polyacrylamide gel electrophoresis; adolescence (12-20); alleles; child (0-11); clinical chemistry; complement pathway; complement receptor; connective tissue disorder; dermatomyositis; gene expression; gene rearrangement; genetic polymorphism; histocompatibility gene; histocompatibility typing; human genetic material tag; juvenile rheumatoid arthritis; nucleic acid hybridization; nucleic acid probes; nucleic acid sequence; polymerase chain reaction; protein structure function; restriction fragment length polymorphism; southern blotting; statistics /biometry; systemic lupus erythematosus; tenascin

The long term goal of this proposal is to identify and elucidate the genetic variants of elements involved in the complement activation and/or in the dissolution of immune complexes (IC) in rheumatic diseases. It seeks to determine the polymorphic or deficient allotypes of complement components C4 and C2 and complement receptor type 1 (CR1) in four selected groups of rheumatic diseases patients: juvenile rheumatic arthritis (JRA), systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and juvenile dermatomyositis (JDMS). The proposal also aims to characterize the gene organization of the HLA class III region and to identify susceptibility genes involved in these pediatric rheumatic diseases. The rationale for this study is the essential roles C4, C2 and CR1 in complement activation and in the solubilization and clearance of lC, C4 and C2 are located in the class III region of the HLA. Several novel genes located neighboring to C4 have been discovered. These genes may be relevant in the pathogenesis of rheumatic diseases, particularly the extracellular matrix protein tenascin-X (Tn-XB). We have discovered complex patterns of gene deletions, rearrangements and polymorphisms of the twelve genes and gene segments between 02 and Tn-XB. This proposal represents a comprehensive study to determine variants of the dynamic HLA class III region on the etiology of pediatric rheumatic diseases. A large cohort of rheumatic disease patients is available to this study. The three specific aims are: I. To determine variations in gene organization of twelve genes/gene segments present in the complement C2 to tenascin Tn-XB loci in the HLA class Ill region in rheumatic disease patients and in controls; II. To determine if there are C4A and/or C4B allelic polymorphisms and other genes in the C2/Tn-XB region that are associated with SLE and other rheumatic disease patients; and, III. To determine if differences in the primary structure (ie. amino acid sequence) of CR1, resulting in differences in membrane stability or function, are associated with rheumatic disease patients. Results obtained by molecular genetic studies will be analyzed statistically to determine their association with disease groups and subsets. This study will provide important information on the role of the HLA and complement on the etiology of SLE, JRA and other pediatric rheumatic diseases. It may also facilitate the differential diagnosis and influence the treatment of these chronic diseases.

该提案的长期目标是确定并阐明 参与补体激活的元件的遗传变异和/或 风湿病中免疫复合物 (IC) 的溶解。它 试图确定补体的多态性或缺陷同种异型 四种成分中的 C4 和 C2 以及补体受体 1 型 (CR1) 选定的风湿病患者群体：青少年风湿病患者 关节炎 (JRA)、系统性红斑狼疮 (SLE)、混合结缔组织 组织疾病（MCTD）和幼年皮肌炎（JDMS）。提案 还旨在表征 HLA III 类的基因组织 区域并确定与这些儿科相关的易感基因 风湿性疾病。这项研究的基本原理是重要的作用 C4、C2 和 CR1 在补体激活和溶解中的作用 lC、C4和C2的间隙位于III类区域 HLA。已经发现了几个位于 C4 附近的新基因。 这些基因可能与风湿性疾病的发病机制有关， 特别是细胞外基质蛋白生腱蛋白-X (Tn-XB)。我们有 发现了基因删除、重排的复杂模式 02和Tn-XB之间的12个基因和基因片段的多态性。 该提案代表了一项综合研究，旨在确定 动态 HLA III 区与小儿风湿病病因学的关系 疾病。大量风湿病患者可以 这项研究。这三个具体目标是： I. 确定 补体中存在的十二个基因/基因片段的基因组织 风湿病患者 HLA III 类区域中的 C2 至生腱蛋白 Tn-XB 位点 疾病患者和对照者；二.判断是否有C4A 和/或 C4B 等位基因多态性和 C2/Tn-XB 区域中的其他基因 与系统性红斑狼疮和其他风湿性疾病患者相关；和， 三．确定一级结构（即氨基酸）是否存在差异 CR1 的序列），导致膜稳定性的差异或 功能，与风湿病患者有关。结果 通过分子遗传学研究获得的结果将进行统计分析 确定它们与疾病组和子集的关联。这项研究 将提供有关 HLA 和补体作用的重要信息 SLE、JRA 和其他小儿风湿性疾病的病因学。它 也可能有助于鉴别诊断并影响 治疗这些慢性疾病。