Localizing functional variants in SLE susceptibility genes

描述（由申请人提供）：系统性红斑狼疮（SLE或狼疮）是一种复杂的自身免疫性疾病，其特点是由致病性自身抗体产生引起的广泛临床表现。SLE对女性和某些种族的影响不成比例。与欧美人相比，亚洲人、非洲裔美国人和西班牙裔美国人的SLE患病率高3-5倍，临床表现更严重。遗传因素强烈影响狼疮的发展和进展，全基因组关联研究（GWAS）已经确定了超过40种与狼疮易感性相关的遗传关联，其中大部分来自欧洲血统的个体。为了了解导致SLE疾病亚表型的生物学机制，描述GWAS关联信号的功能变异是至关重要的。然而，精确地描述功能变体一直是主要的挑战，因为来自GWAS的相关变体通常是实际功能变体所在的单倍型的“标签”。我们的研究团队已经获得了超越GWAS所需的经验、专业知识、资源和基础设施，以加速发现和表征这些信号背后的因果变异。我们已经成功地确定了ITGAM基因的因果变异及其功能后果。我们建议研究四个sle1易感基因，IFIH1、ETS1、IKZF1和PRDM1，这些基因与多种自身免疫性疾病的易感性有关，表明它们在自身免疫中具有更广泛的作用。我们的主要目标是确定这些基因的功能变异，并解释它们与SLE及其临床亚表型的因果关系。在目标1中，我们将整合来自1000个基因组的多种族队列的基因型和测序数据，同时利用人群之间的遗传差异。这些分析将从我们的候选基因中确定最可能的功能变异，并阐明SLE临床亚表型的遗传和临床异质性。在目标2中，我们将预测和验证候选变体的功能影响。我们将首先从ENCODE数据中识别功能元件，包括蛋白质编码序列、转录调控区、伴随的染色质状态、表观遗传标记和eQTL信号。生物信息学和分子建模将指导后续的原代和培养细胞实验，以验证候选细胞的功能效应

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.