Molecular Genetics of BAT Genes and SLE Risk

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的复杂相互作用引起的。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物（MHC）基因座参与SLE发病机制，最初由连锁和关联研究提出，最近由全基因组关联研究（GWAS）证实。我们对最近GWAS数据的后续工作表明，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/炎症性疾病的关联。总之，这些观察结果为全面研究4种BAT基因（BAT 1，BAT 2，BAT 3，BAT 4）在SLE和相关表型的发病机制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数据和/或已发表的研究表明，BAT 1 -4区域含有与SLE和相关表型相关的其他基因。我们将结合重测序、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，以表征影响SLE风险的BAT 1 -4区域基因的功能变体。这些基因将在选定的SLE病例和对照中重新测序，以分类常见和罕见变异，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。生物信息学工具、公开可用的数据库和RNA实验的组合将用于确定显著变体的功能相关性。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，而且还有助于阐明其他具有重叠病理学的MHC相关自身免疫性疾病。 公共卫生相关性：本研究的目的是综合分析4个BAT（HLA-B相关转录本）基因（BAT 1，BAT 2，BAT 3，BAT 4）和位于BAT 1 -4区域内的其他基因与系统性红斑狼疮（SLE）风险的关联性，使用重测序、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。研究结果可能为SLE相关的病理机制提供有用的见解，也可能揭示其他MHC相关的自身免疫性疾病与重叠的病理。

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.