Functional Mechanisms of Causal Variants in Systemic Lupus Erythematosus

描述（由申请人提供）：系统性红斑狼疮（SLE）的特征是对大量自身抗原的免疫耐受性丧失，导致系统性器官炎症。尽管经过数十年的研究，狼疮的潜在遗传基础显然是复杂的，仍然知之甚少。使用全基因组关联（GWAS）方法对人类基因组进行无偏倚筛选，已成功地在主要为欧洲血统的SLE病例对照组中鉴定出30多个基因组区域。尽管与SLE相关的新基因激增，但GWAS方法无法识别统计学关联基础的精确因果变异，从而阻碍了将这些信息功能性地转化为SLE患者诊断和管理的改善。 我们的实验室已经获得了必要的资源和经验，超越了GWAS的因果变异发现和表征。作为我们成功的一个衡量标准，我们已经确定了TNFAIP 3和BLK区域中与SLE相关的功能变体。本项目的主要目的是确定三个SLE风险基因TNIP 1、UBE 2L 3和IRF 5中致病变异和单倍型的功能机制。本文提出的工作将扩大SLE风险基因的数量，这些基因的功能性致病变异是已知和理解的。对致病变异和携带它们的单倍型的机械理解是非常必要的，以制定一个令人信服的SLE遗传景观的观点，并促进SLE诊断和治疗的进展。 为了这项提案，我们组建了一支技术熟练的研究人员团队，他们跨越了各种科学和临床学科，包括风湿病学、内分泌学、肾脏学、遗传学、分子生物学、蛋白质组学、生物统计学和生物信息学。该项目的关键资源是OMRF独有的，并由我们的团队在过去五年中开发，包括：1）4个主要种族人群中超过8,300例SLE病例和7,400例对照的高密度SNP数据集，2）超过700例欧洲和非洲血统受试者的靶向重测序数据库，3）一个由1000多名当地研究受试者组成的数据库，这些受试者广泛同意参与遗传研究，并对所有已知的SLE风险基因进行完全基因分型，4）用于患者特征描述和样本采集的最先进的临床设施，以及5）获得尖端的分子和基因组技术。我们相信，这些丰富的数据集和我们积累的经验使我们的团队能够领导SLE因果变异发现的努力。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is characterized by a loss of immunologic tolerance to a multitude of self-antigens that results in systemic organ inflammation. Despite decades of research, the underlying genetic basis of lupus is clearly complex and remains poorly understood. Unbiased screens of the human genome using genome-wide association (GWAS) approaches have successfully identified over 30 genomic regions in SLE case-control groups primarily of European ancestry. Despite this surge of new genes associated with SLE, the GWAS approach has been unable to identify the precise causal variants that underlie the statistical associations, thus hampering functional translation of this information into improvements in the diagnosis and management of patients with SLE. Our laboratory has acquired the resources and experience necessary to move beyond GWAS to causal variant discovery and characterization. As a measure of our success we have identified functional variants responsible for association with SLE in the region of TNFAIP3 and BLK. The primary objective of this project is to define the functional mechanisms of causal variants and haplotypes in three SLE risk genes, TNIP1, UBE2L3 and IRF5. The work proposed herein will expand the number of SLE risk genes for which functional causal variants are known and understood. A mechanistic understanding of causal variants and the haplotypes that carry them is critically needed to formulate a cogent view of the SLE genetic landscape and to catalyze progress in the diagnosis and treatment of SLE. For this proposal, we have assembled a team of skilled investigators that span a variety of scientific and clinical disciplines including rheumatology, endocrinology, nephrology, genetics, molecular biology, proteomics, biostatistics and bioinformatics. Key resources available to this project that are unique to OMRF and developed by our group over the previous five years include: 1) high density SNP datasets in over 8,300 SLE cases and 7,400 controls across 4 major racial populations, 2) a targeted resequencing database of over 700 subjects of European and African ancestry, 3) an assembled database of over 1000 locally available research subjects broadly consented for participation in genetic studies and completely genotyped for all known SLE risk genes, 4) new state-of-the-art clinical facilities for patient characterization and sample procurement, and 5) access to cutting edge molecular and genomic technologies. We are confident that these rich datasets and our cumulative experience uniquely position our group to lead the effort in causal variant discovery in SLE.