TNFAIP3 (A20) and Susceptibility to Systemic Lupus Erythematosus

TNFAIP3 (A20) 与系统性红斑狼疮的易感性

• 批准号: 8104061
• 负责人: Patrick M Gaffney
• 金额: $ 65.6万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-07 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8104061
• 关键词: 3' Untranslated Regions; 6q21; A20 protein; African American; Alleles; American; Antigen-Antibody Complex; Asians; Attenuated; Autoantibodies; Autoimmune Diseases; Autoimmunity; Bioinformatics; Biology; Chromosomes; Code; DNA; DNA Resequencing; Data; Defect; Diagnosis; Disease; Engineering; Enzymes; Ethnic group; European; Exons; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Haplotypes; Healthcare; Heterozygote; Hispanics; Human; Human Genome; Immune system; Inflammation; Inflammatory; Interleukin-1; Laboratories; Lead; Length; Life; Ligands; Maps; Messenger RNA; Meta-Analysis; Modeling; Monitor; Mus; NF-kappa B; Organ; Patients; Phenotype; Population; Positioning Attribute; Predisposition; Production; Proteins; Publishing; Regulation; Resolution; Risk; Secure; Signal Transduction; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Structure; Systemic Lupus Erythematosus; TNF gene; Technology; Testing; Tumor Necrosis Factor-alpha; Ubiquitin; Untranslated Regions; Update; Variant; Work; attenuation; base; case control; cohort; density; genetic association; genetic variant; novel; promoter; public health relevance; racial and ethnic; response; sample collection

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease characterized by autoantibody production and immune complex formation. Genetic predisposition to SLE has been well characterized with over two decades of work in human and murine models, however the precise genetic variants responsible have, with few exceptions, remained elusive. With the advent of high-density single nucleotide polymorphism (SNP) maps based on the complete sequence of the human genome and the ability to genotype these polymorphisms using high density arrays in thousand of subjects, the genetic landscape of SLE is being revealed with unprecedented resolution. Recently published work from our laboratory has identified and confirmed a convincing novel association with TNFAIP3 (A20), a critical negative regulator of NF-kB signaling. New preliminary data presented in this amended proposal demonstrates that the TNFAIP3 association is convincingly replicated in multiple independent European-derived SLE sample collections with a meta-analysis P-value of 1.51x10-15 (OR=2.09) for the best marker, rs5029939. Through imputation, we identify 11 new associated variants and define the limits of the TNFAIP3 SLE risk haplotype to a 109 kb DNA segment that spans the TNFAIP3 coding region. Using a coordinated bioinformatics approach, we evaluated the functional potential for each SNP on the risk haplotype and determined that it is unlikely that any of the currently typed or imputed SNPs are responsible for the genetic association. Finally, preliminary functional data suggest that the SLE risk alleles in the TNFAIP3 locus result in a defect in TNFAIP3 expression and regulation of NF-kB activation. The primary objectives of this project are focused on isolating the precise variant responsible for the association in the region of TNFAIP3 in human SLE. We will do this by testing the hypothesis that the association extends to SLE cohorts of non-European ancestry. We will exploit differences in population haplotype structure to narrow the SLE risk interval using a trans-racial mapping approach. In parallel, we will deeply resequence the region, focusing first on promoter, exons and UTR regions using conventional sequencing. We will, however, rapidly employ sequence capture and massively parallel sequencing technology to resequence the entire risk haplotype when fully operational. Finally, we will test the "expression phenotype" hypothesis and the "F127C" hypothesis as likely functional effects of the SLE associated risk haplotype. When complete, we expect to have identified the precise variant(s) responsible for association with SLE in European American, African American, Asian and Hispanic populations. We expect to have an initial mechanistic understanding for how the associated variants alter A20 structure and function in a manner that predisposes to autoimmunity. These results should add significantly to our understanding of the genetic and pathophysiologic basis of SLE and lead to improvements for patients with SLE and related autoimmune disorders for which variants in TNFAIP3 portend risk. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus is a severe, debilitating autoimmune disease that represents a significant healthcare burden worldwide. Our study will characterize a genetic association between SLE and TNFAIP3, a gene critical for controlling inflammation and immune system function. This work has the potential to lead to new treatments for SLE and to new tests for diagnosing and monitoring the disease.

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种炎症性自身免疫性疾病，其特征是自身抗体产生和免疫复合物形成。SLE的遗传易感性已经在人类和小鼠模型中进行了20多年的研究，但除少数例外外，确切的遗传变异仍然难以捉摸。随着基于人类基因组全序列的高密度单核苷酸多态性（SNP）图谱的出现，以及使用高密度阵列在数千名受试者中对这些多态性进行基因分型的能力，SLE的遗传景观正以前所未有的分辨率被揭示。我们实验室最近发表的工作已经确定并证实了与TNFAIP 3（A20）的令人信服的新关联，TNFAIP 3（A20）是NF-kB信号传导的关键负调节因子。本修订提案中提供的新的初步数据表明，TNFAIP 3相关性在多个独立的欧洲来源的SLE样本收集中令人信服地重复，最佳标志物rs 5029939的荟萃分析P值为1.51x10-15（OR=2.09）。通过插补，我们确定了11个新的相关变异，并确定了TNFAIP 3 SLE风险单倍型的限制，跨越TNFAIP 3编码区的109 kb的DNA片段。使用协调的生物信息学方法，我们评估了风险单倍型上每个SNP的功能潜力，并确定目前分型或估算的任何SNP都不太可能对遗传关联负责。最后，初步的功能数据表明，在TNFAIP 3基因座中的SLE风险等位基因导致TNFAIP 3表达和调节NF-κ B活化的缺陷。该项目的主要目标是分离负责人类SLE中TNFAIP 3区域相关性的精确变体。我们将通过检验这种关联延伸到非欧洲血统的SLE队列的假设来做到这一点。我们将利用人群单倍型结构的差异，使用跨种族作图方法缩小SLE风险区间。与此同时，我们将对该区域进行深度重新测序，首先使用常规测序重点关注启动子、外显子和UTR区域。然而，我们将迅速采用序列捕获和大规模并行测序技术，在完全运行时对整个风险单倍型进行重新测序。最后，我们将检验“表达表型”假说和“F127 C”假说作为SLE相关风险单倍型的可能功能效应。当完成时，我们期望已经确定了负责与欧洲裔美国人，非洲裔美国人，亚洲人和西班牙裔人群中的SLE相关的精确变异。我们希望对相关变体如何以易患自身免疫的方式改变A20的结构和功能有初步的机制理解。这些结果将大大增加我们对SLE遗传和病理生理基础的理解，并改善SLE和TNFAIP 3变异预示风险的相关自身免疫性疾病患者。 公共卫生关系：系统性红斑狼疮是一种严重的，使人衰弱的自身免疫性疾病，在全球范围内造成了重大的医疗负担。我们的研究将描述SLE和TNFAIP 3之间的遗传关联，TNFAIP 3是控制炎症和免疫系统功能的关键基因。这项工作有可能导致SLE的新治疗方法以及诊断和监测疾病的新测试。