Localizing functional variants in SLE susceptibility genes

定位 SLE 易感基因的功能变异

• 批准号: 8995183
• 负责人: Swapan K. Nath
• 金额: $ 21.44万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8995183
• 关键词: Address; Affect; African American; Age; American; Antigen-Antibody Complex; Apoptosis; Asians; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biocompatible Materials; Bioinformatics; Biological; Biological Process; Candidate Disease Gene; Cell Maturation; Chromatin; Clinical; Code; Complement Activation; Complex; Computer Simulation; Cultured Cells; Data; Deposition; Development; Disease; ETS1 gene; Elements; Epigenetic Process; Ethnic group; European; Evaluation; Future; Gene Expression; Gene Proteins; Gene Targeting; Genes; Genetic; Genetic Research; Genome; Genotype; Goals; Haplotypes; Health; Heterogeneity; High Prevalence; Hispanic Americans; Hispanics; ITGAM gene; Individual; Inflammation; Intercistronic Region; Knowledge; Lead; Link; Linkage Disequilibrium; Lupus; Lupus Nephritis; Maps; Medical Genetics; Modeling; Molecular; Molecular Models; Morbidity - disease rate; Nucleic Acid Regulatory Sequences; Organ; PRDM1 gene; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Phenotype; Physiological; Population; Population Heterogeneity; Predisposition; Prevalence; Primary Cell Cultures; Production; Proteins; Research; Research Infrastructure; Resources; Role; Sampling; Signal Transduction; Structure; Susceptibility Gene; Systemic Lupus Erythematosus; TNFSF4 gene; Techniques; Therapeutic Intervention; Tissues; Variant; Woman; admixture mapping; anti-dsDNA autoantibody; base; cell type; cohort; curative treatments; design; ethnic diversity; ethnic minority population; experience; follow-up; genetic association; genetic information; genetic variant; genome wide association study; genome-wide; molecular modeling; mortality; novel; protein function; research study; therapeutic target; viral resistance

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE or lupus) is a complex autoimmune disease characterized by a broad spectrum of clinical manifestations that arise from pathogenic autoantibody production. SLE disproportionately affects women and certain ethnic groups. Asians, African-Americans, and Hispanics show 3-5 fold higher prevalence and more severe clinical manifestations of SLE compared to European-Americans. Genetic factors strongly influence lupus development and progression, and genome-wide association studies (GWAS) have identified over 40 genetic associations for SLE susceptibility, mostly from the individuals with European ancestry. In order to understand the biological mechanisms that lead to disease sub-phenotypes in SLE, it is crucial to delineate the functional variants responsible for GWAS association signals. However, precisely delineating functional variants has been a major challenge, since associated variants from GWAS are often ''tags'' for haplotypes on which the actual functional variants reside. Our research team has acquired the experience, expertise, resources and infrastructure necessary to move beyond GWAS to accelerate discovery and characterization of the causal variants underlying these signals. We have successfully identified causal variants and their functional consequences in the ITGAM gene. We propose studying four SLE-susceptibility genes, IFIH1, ETS1, IKZF1, and PRDM1, that have been implicated in susceptibility to multiple autoimmune diseases, suggesting their broader roles in autoimmunity. Our primary goals are to define functional variants in these genes and explain their causal relationships with SLE and its clinical sub-phenotypes. In Aim 1 we will integrate our genotype and sequencing data from multi-ethnic cohorts with 1000 Genomes, while leveraging genetic differences between populations. These analyses will identify the most likely functional variants from our candidate genes, and elucidate genetic and clinical heterogeneity with SLE clinical sub-phenotypes. In Aim 2 we will predict and validate functional effects for candidate variants. We will first identify functional elements from ENCODE data, including protein coding sequence, transcriptional regulatory regions, attendant chromatin states, epigenetic marks, and eQTL signals. Bioinformatics and molecular modeling will guide follow-up experiments in primary and cultured cells to validate the functional effects of candidate variants on gene expression and protein function. Most of the data and samples for conducting this proposal are already available to us. With our integrated research strategy, cumulative expertise, strong track record, available biomaterials, resources and infrastructure, we have strong potential to successfully complete this project. We expect that this project will identify SLE-associated functional variants and define their effects on relevant biological pathways in order to elucidate the pathogenic mechanisms of lupus. Ultimately, this project could provide a basis for future therapeutic interventions for SLE and other autoimmune diseases influenced by these genes.

描述（由申请人提供）：全身性红斑狼疮（SLE或狼疮）是一种复杂的自身免疫性疾病，其特征是多种临床表现，这是由致病性自身抗体产生引起的。 SLE不成比例地影响妇女和某些种族。与欧美人相比，亚洲人，非裔美国人和西班牙裔SLE的患病率更高3-5倍。遗传因素强烈影响狼疮的发育和进展，以及全基因组关联研究（GWAS）已确定了40多个遗传关联以实现SLE敏感性，主要来自具有欧洲血统的人。为了了解导致SLE疾病亚表征的生物学机制，描述负责GWAS关联信号的功能变体至关重要。但是，精确描绘功能变体一直是一个主要的挑战，因为GWAS的相关变体通常是对实际功能变体所存在的单倍型的“标签”。我们的研究团队已经获得了超越GWAS的经验，专业知识，资源和基础设施，以加速这些信号基础的因果变体的发现和表征。我们已经成功地鉴定出在ITGAM基因中的因果变异及其功能后果。我们建议研究四个SLE敏感性基因IFIH1，ETS1，IKZF1和PRDM1，这与对多种自身免疫性疾病的敏感性有关，这表明它们在自身免疫中的广泛作用。我们的主要目标是定义这些基因中的功能变异，并解释其与SLE及其临床子表型的因果关系。在AIM 1中，我们将与1000个基因组相结合的基因型和测序数据，同时利用种群之间的遗传差异。这些分析将从我们的候选基因中确定最可能的功能变异，并通过SLE临床亚表格型阐明遗传和临床异质性。在AIM 2中，我们将预测并验证候选变体的功能效应。我们将首先从编码数据中确定功能元素，包括蛋白质编码序列，转录调节区域，随之而来的染色质状态，表观遗传标记和EQTL信号。生物信息学和分子建模将指导初级和培养细胞中的随访实验，以验证候选者的功能效应 基因表达和蛋白质功能的变体。进行此提案的大多数数据和样本已经为我们提供。借助我们综合的研究策略，累积专业知识，强大的往绩，可用的生物材料，资源和基础设施，我们有很大的潜力可以成功完成该项目。我们预计该项目将识别与SLE相关的功能变体，并定义它们对相关生物途径的影响，以阐明狼疮的致病机制。最终，该项目可以为受这些基因影响的SLE和其他自身免疫性疾病的未来治疗干预提供基础。

项目成果

High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci.

• DOI: 10.1136/annrheumdis-2013-204749
• 发表时间: 2015-03
• 期刊: Annals of the rheumatic diseases
• 影响因子: 27.4
• 作者: Kim K;Bang SY;Lee HS;Cho SK;Choi CB;Sung YK;Kim TH;Jun JB;Yoo DH;Kang YM;Kim SK;Suh CH;Shim SC;Lee SS;Lee J;Chung WT;Choe JY;Shin HD;Lee JY;Han BG;Nath SK;Eyre S;Bowes J;Pappas DA;Kremer JM;Gonzalez-Gay MA;Rodriguez-Rodriguez L;Ärlestig L;Okada Y;Diogo D;Liao KP;Karlson EW;Raychaudhuri S;Rantapää-Dahlqvist S;Martin J;Klareskog L;Padyukov L;Gregersen PK;Worthington J;Greenberg JD;Plenge RM;Bae SC
• 通讯作者: Bae SC