Molecular Genetics of BAT Genes and SLE Risk

BAT 基因的分子遗传学和 SLE 风险

基本信息

批准号：
7940839
负责人：
F. Yesim Demirci
金额：
$ 54.72万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7940839
关键词：
3&apos Flanking Region 6p21.3 Accounting Affect Alleles Antiphospholipid Antibodies Apoptosis Autoantibodies Autoimmune Diseases Autoimmune Process Base Sequence Behavior Bioinformatics Candidate Disease Gene Cardiovascular Diseases Carotid Artery Plaques Cataloging Catalogs Cell Line Chromosomes Chronic Complex DNA Resequencing Data Databases Disease Environmental Risk Factor Family Female of child bearing age Gene Expression Gene Expression Profile Gene Frequency Genes Genetic Genetic Predisposition to Disease Genetic Variation Genotype Goals HLA-B Antigens HLA-DRB1 Haplotypes Immune Immunity Individual Inflammation Inflammatory Knowledge Life Light Link Linkage Disequilibrium Literature Lupus Nephritis Major Histocompatibility Complex Maps Measures Mediating Minor Molecular Genetics Nephritis Organ Parents Pathologic Pathology Patients Phenotype Play Predisposition Publishing RNA RNA Databases RNA Splicing RNA Stability Rare Diseases Regulation Reporting Resources Rheumatoid Arthritis Risk Role Sampling Screening procedure Siblings Single Nucleotide Polymorphism Structure Systemic Lupus Erythematosus TNF gene Techniques Testing Thick Time Transcript Variant Work base cardiovascular disorder risk case control clinically relevant cost density follow-up genetic variant genome wide association study genome-wide insight intima media premature atherosclerosis protein structure public health relevance research study response tool trait

项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a prototypic, multisystem, autoimmune-mediated chronic inflammatory disease that primarily targets women of child-bearing age. It has a complex genetic basis and is caused by a complex interaction of environmental factors and multiple genetic susceptibility loci. There is compelling evidence for the involvement of the Major Histocompatibility Complex (MHC) locus on chromosome 6p21.3 in SLE ethiopathogenesis, as suggested initially by linkage and association studies and confirmed recently by genome-wide association studies (GWAS). Our follow-up work on the data from a recent GWAS indicates that BAT genes residing within MHC class III region are significantly and independently associated with SLE risk and lupus nephritis. Furthermore, there is extensive literature knowledge documenting the functional and clinical relevance of BAT genes, including their involvement in immune/inflammation responses, apoptosis, and SLE-related gene expression signature, and their association with rheumatoid arthritis and other immune/inflammatory diseases. Taking together, these observations provide a strong rationale to comprehensively examine the role of 4 BAT genes (BAT1, BAT2, BAT3, BAT4) in the ethiopathogenesis of SLE and related phenotypes. Clustering of functionally-related genes is the hallmark of the MHC locus and the GWAS data and/or published studies implicate that the BAT1-4 region harbors additional genes that are also relevant to SLE and related phenotypes. We will use a combination of resequencing, genotyping, and functional analysis techniques in conjunction with a variety of databases and bioinformatics tools in order to characterize the functional variants of the genes in the BAT1-4 region that influence the SLE risk. These genes will be resequenced in selected SLE cases and controls to catalogue both common and rare variation, followed by screening of common tag SNPs and rare variants in the entire discovery sample and replication of significant associations in two independent replication samples. A combination of bioinformatics tools, publicly available databases, and RNA experiments will be used to determine the functional relevance of significant variants. The data generated from this study is expected not only to increase our understanding about SLE-related disease mechanisms but also to shed light on other MHC-linked autoimmune diseases with overlapping pathology. PUBLIC HEALTH RELEVANCE: The objective of this study is to comprehensively analyze the association of four BAT (HLA-B associated transcript) genes (BAT1, BAT2, BAT3, BAT4) and other genes that lie within the BAT1-4 region with the risk of systemic lupus erythematosus (SLE), using a combination of resequencing, genotyping, and functional analysis techniques in conjunction with a variety of publicly available databases and bioinformatics tools. The study results are likely to provide useful insights into SLE-related pathologic mechanisms and may also shed light on other MHC-linked autoimmune diseases with overlapping pathology.

描述（由申请人提供）：全身性红斑狼疮（SLE）是一种原型，多系统的，自身免疫性介导的慢性炎症性疾病，主要针对童年的妇女。它具有复杂的遗传基础，是由环境因素和多个遗传易感性基因座的复杂相互作用引起的。如最初是通过连锁和关联研究提出的，有令人信服的证据表明，主要组织相容性复合物（MHC）基因座（MHC）基因座（MHC）基因座（MHC）基因座（MHC）基因座（MHC）基因座（MHC）基因座（MHC）基因座（MHC）基因座（MHC）基因座（MHC）基因座（MHC）在SLE征原机中的参与。我们对最近GWA的数据的后续工作表明，位于MHC III类区域内的BAT基因与SLE风险和狼疮性肾炎有显着和独立的相关性。此外，有广泛的文献知识记录了蝙蝠基因的功能和临床相关性，包括它们参与免疫/炎症反应，凋亡和与SLE相关的基因表达签名以及与类风湿关节炎和其他免疫/炎症性疾病的关联。综上所述，这些观察结果提供了有力的理由，可以全面研究4个BAT基因（BAT1，BAT2，BAT3，BAT4）在SLE和相关表型的埃塞哥部生成中的作用。功能相关基因的聚类是MHC基因座的标志，GWAS数据和/或已发表的研究暗示，BAT1-4区域具有与SLE和相关表型有关的其他基因。我们将结合重新配置，基因分型和功能分析技术与多种数据库和生物信息学工具结合使用，以表征影响SLE风险的BAT1-4区域中基因的功能变体。这些基因将在选定的SLE病例中重新计算，并将对照组成共同变化和罕见变化，然后在整个发现样本中筛选常见的TAG SNP和稀有变体，并在两个独立复制样本中复制显着关联。生物信息学工具，公开可用数据库和RNA实验的结合将用于确定重要变体的功能相关性。期望从这项研究中产生的数据不仅可以提高我们对与SLE相关疾病机制的理解，而且还可以阐明其他与MHC连接的自身免疫性疾病，并具有重叠的病理学。 PUBLIC HEALTH RELEVANCE: The objective of this study is to comprehensively analyze the association of four BAT (HLA-B associated transcript) genes (BAT1, BAT2, BAT3, BAT4) and other genes that lie within the BAT1-4 region with the risk of systemic lupus erythematosus (SLE), using a combination of resequencing, genotyping, and functional analysis techniques in conjunction with a variety of publicly available databases and生物信息学工具。该研究结果可能会为与SLE相关的病理机制提供有用的见解，并且还可以揭示出具有重叠病理学的其他MHC连接的自身免疫性疾病。