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：
8197710
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/8197710
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）：系统性红斑狼疮 (SLE) 是一种原型、多系统、自身免疫介导的慢性炎症性疾病，主要针对育龄妇女。它具有复杂的遗传基础，是由环境因素和多个遗传易感位点复杂的相互作用引起的。有令人信服的证据表明，染色体 6p21.3 上的主要组织相容性复合体 (MHC) 位点参与 SLE 发病机制，正如连锁和关联研究最初所表明的那样，最近全基因组关联研究 (GWAS) 也证实了这一点。我们对最近 GWAS 数据的后续研究表明，位于 MHC III 类区域内的 BAT 基因与 SLE 风险和狼疮性肾炎显着且独立相关。此外，有大量文献知识记录了 BAT 基因的功能和临床相关性，包括它们参与免疫/炎症反应、细胞凋亡和 SLE 相关基因表达特征，以及它们与类风湿性关节炎和其他免疫/炎症疾病的关联。综上所述，这些观察结果为全面研究 4 个 BAT 基因（BAT1、BAT2、BAT3、BAT4）在 SLE 发病机制和相关表型中的作用提供了强有力的依据。功能相关基因的聚类是 MHC 基因座的标志，GWAS 数据和/或已发表的研究表明 BAT1-4 区域包含也与 SLE 和相关表型相关的其他基因。我们将结合使用重测序、基因分型和功能分析技术以及各种数据库和生物信息学工具来表征 BAT1-4 区域中影响 SLE 风险的基因的功能变异。这些基因将在选定的 SLE 病例和对照中进行重新测序，以对常见和罕见变异进行分类，然后在整个发现样本中筛选常见标签 SNP 和罕见变异，并在两个独立复制样本中复制显着关联。将结合生物信息学工具、公开数据库和 RNA 实验来确定重要变异的功能相关性。这项研究产生的数据不仅有望增加我们对 SLE 相关疾病机制的理解，还能揭示其他具有重叠病理学的 MHC 相关自身免疫性疾病。公共健康相关性：本研究的目的是全面分析四种 BAT（HLA-B 相关转录本）基因（BAT1、BAT2、BAT3、BAT4）和 BAT1-4 区域内的其他基因与以下风险的关联：系统性红斑狼疮 (SLE)，结合使用重测序、基因分型和功能分析技术，并结合各种公开可用的数据库和生物信息学工具。该研究结果可能为 SLE 相关病理机制提供有用的见解，也可能为其他具有重叠病理学的 MHC 相关自身免疫性疾病提供线索。