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.

本提案的长期目标是确定和阐明