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）的特点是对大量自身抗原失去免疫耐受性，导致全身器官炎症。尽管几十年的研究，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筛选，已成功地在主要为欧洲血统的SLE病例对照组中确定了30多个基因组区域。尽管与SLE相关的新基因激增，但GWAS方法仍无法确定统计关联背后的精确因果变异，从而阻碍了将这些信息功能性转化为改善SLE患者的诊断和管理。我们的实验室已经获得了必要的资源和经验，可以超越GWAS，进行因果变异的发现和表征。作为我们成功的衡量标准，我们已经确定了TNFAIP3和BLK区域与SLE相关的功能变异。本项目的主要目的是确定三种SLE风险基因TNIP1、UBE2L3和IRF5的因果变异和单倍型的功能机制。本文提出的工作将扩大功能性因果变异已知和理解的SLE风险基因的数量。对因果变异和携带它们的单倍型的机制理解是非常必要的，以便对SLE的遗传景观形成一个令人信服的观点，并促进SLE的诊断和治疗进展。为了这项提案，我们组建了一支技术娴熟的研究团队，他们跨越了各种科学和临床学科，包括风湿病学、内分泌学、肾脏病学、遗传学、分子生物学、蛋白质组学、生物统计学和生物信息学。本项目可利用的OMRF独有的、由我们集团在过去五年中开发的关键资源包括：1) 4个主要种族人群中超过8300例SLE病例和7400例对照的高密度SNP数据集，2)超过700名欧洲和非洲血统受试者的靶向重测序数据库，3)超过1000名当地可用的研究受试者的组装数据库，广泛同意参与遗传研究，并对所有已知的SLE风险基因进行完整的基因分型，4)新的最先进的临床设施，用于患者表征和样本采购。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累积的经验使我们的团队在SLE因果变异发现方面处于独特的地位。

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.