Molecular Genetics of BAT Genes and SLE Risk

描述(申请人提供)：系统性红斑狼疮(SLE)是一种典型的、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，是环境因素和多个遗传易感基因座复杂相互作用的结果。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)基因座参与了SLE的民族致病，最初是由连锁和关联研究提出的，最近被全基因组关联研究(GWAS)证实。我们的后续工作来自最近的GWAS的数据表明，位于MHC III类区域的BAT基因与SLE风险和狼疮性肾炎显著且独立相关。此外，有大量的文献知识记录了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/炎症性疾病的关系。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的民族致病机制和相关表型中的作用提供了强有力的理论基础。功能相关基因的聚集是MHC基因座的标志，Gwas的数据和/或已发表的研究表明，BAT1-4区域包含其他与SLE和相关表型相关的基因。我们将结合重测序、基因分型和功能分析技术，结合各种数据库和生物信息学工具，以确定影响系统性红斑狼疮风险的BAT1-4区域基因的功能变异。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，并在两个独立的复制样本中复制显著关联。将使用生物信息学工具、公开可用的数据库和RNA实验的组合来确定重要变体的功能相关性。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，还将有助于揭示其他与MHC相关的自身免疫性疾病的重叠病理。 公共卫生相关性：本研究的目的是综合运用重新测序、基因分型和功能分析技术，结合各种公开可用的数据库和生物信息学工具，全面分析四个BAT(人类白细胞抗原B相关转录本)基因(BAT1、BAT2、BAT3、BAT4)和位于BAT1-4区域的其他基因与系统性红斑狼疮(SLE)风险的关联。研究结果可能为SLE相关的病理机制提供有用的见解，也可能为其他与MHC相关的自身免疫性疾病提供重叠的病理基础。

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.