Functional Mechanisms of Causal Variants in Systemic Lupus Erythematosus

描述(申请人提供)：系统性红斑狼疮(SLE)的特征是对多种自身抗原失去免疫耐受性，从而导致全身器官炎症。尽管经过了几十年的研究，狼疮的潜在遗传基础显然是复杂的，而且仍然知之甚少。使用全基因组关联(GWAS)方法对人类基因组进行无偏筛选，已经成功地在主要是欧洲血统的SLE病例对照组中识别了30多个基因组区域。尽管与系统性红斑狼疮相关的新基因激增，但Gwas方法一直无法识别构成统计关联的确切原因变量，从而阻碍了将这些信息转化为改善SLE患者诊断和管理的功能。我们的实验室已经获得了必要的资源和经验，可以超越GWAs来发现和表征因果变异。作为我们成功的衡量标准，我们已经确定了与TNFAIP3和BLK区域的SLE相关的功能变异。该项目的主要目标是确定三个SLE风险基因TNIP1、UBE2L3和IRF5的因果变异和单倍型的作用机制。本文提出的工作将扩大已知和了解的SLE风险基因的数量。为了形成对SLE遗传格局的令人信服的观点，并催化SLE的诊断和治疗进展，迫切需要从机制上理解因果变异及其携带的单倍型。为了这项提议，我们组建了一支技术娴熟的研究团队，他们涵盖了各种科学和临床学科，包括风湿学、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。OMRF组织在过去五年开发的这一项目特有的主要资源包括：1)针对8,300多名SLE患者和4个主要种族群体的7,400名对照患者的高密度SNP数据集；2)一个包含700多名欧洲和非洲血统受试者的有针对性的重新测序数据库；3)一个包含1000多名当地可用研究对象的集合数据库，该数据库已被广泛批准参与基因研究，并对所有已知的SLE风险基因进行完全基因分型；4)新的一流临床设施，用于患者特征鉴定和样本采集，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的累积经验将使我们的团队在SLE因果变异发现方面发挥独特的领导作用。 公共卫生相关性：系统性红斑狼疮是一种衰弱的自身免疫性疾病，未能跟上新疗法的发展步伐。虽然系统性红斑狼疮的环境诱因仍然是谜，但我们已经目睹了新的基因数据的爆炸性增长。系统性红斑狼疮遗传学的下一个主要挑战将是将这些遗传发现转化为生物机制，以模拟在SLE患者的临床护理中开发新的诊断和治疗方法，该项目致力于这一目标。

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. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus is a debilitating autoimmune disease that has failed to keep pace with the development of new therapies. While the environmental triggers of SLE remain enigmatic, we have witnessed an explosion in new genetic data. The next major challenge for SLE genetics will be to translate these genetic discoveries into biologic mechanisms that simulate the development of new diagnostics and therapeutics in the clinical care of patients with SLE, and this project is dedicated to that objective.