Ikaros family genes and lupus susceptibility across ethnically diverse populations

Ikaros 家族基因和不同种族人群的狼疮易感性

基本信息

批准号：
10238826
负责人：
Joel Marvin Guthridge
金额：
$ 78.17万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238826
关键词：
Abnormal Cell Address Affect African American Alleles American Antigen-Antibody Complex Asians Autoantibodies Autoimmune Diseases B-Lymphocytes Base Sequence Bioinformatics Biological Models Blood Blood Cells CRISPR screen Cell Lineage Cell model Cells Chromatin Chronic Clinical Complement Activation Complex Data Deposition Development Diagnosis Disease Disease Pathway Enhancers Epigenetic Process Ethnic Origin Ethnic group Etiology European Face Family Frequencies Future Gene Expression Gene Family Genes Genetic Genetic Heterogeneity Genotype Goals Haplotypes Health Hematopoiesis Hematopoietic Hematopoietic stem cells Hispanics ITGAM gene Ikaros protein Immune Immune System Diseases Individual Inflammatory Infrastructure Kidney Link Linkage Disequilibrium Lupus Lupus Nephritis Lymphocyte Maps Methods Minority Molecular Morbidity - disease rate Organ Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiological Plant Roots Play Population Population Heterogeneity Predisposition Process Production Protein Family Proteins Refractory Regulation Reporter Reporting Research Resources Risk Role Sampling Serious Adverse Event Signal Transduction Solid Structure System Systemic Lupus Erythematosus T-Lymphocyte Thalidomide Time Tissues Transcriptional Regulation Untranslated RNA Validation Variant Woman Work Zinc Fingers base causal variant cell type clinical heterogeneity clinical phenotype curative treatments deep sequencing density differential expression disease disparity early onset ethnic bias ethnic diversity experience experimental study follow-up genome wide association study genomic locus human model induced pluripotent stem cell lupus cutaneous member molecular phenotype mortality multi-ethnic novel pathogenic autoantibodies risk variant stem cell model transcription factor virtual

项目摘要

Project Summary Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a substantial genetic component. Recent genome-wide association studies (GWAS) have identified SLE associated loci, including IKZF1 and IKZF2, encoded for ikaros and helios proteins, respectively. These proteins play important roles in regulation of differentiation of immune cells important in SLE development and drugs which regulate these protein levels are used to treat refractory cutaneous lupus and nephritis making a strong case for the importance of these genes in SLE. Our recent ImmunoChip-based association study in Asians firmly established IKZF1-SLE association and detected additional independent variants (10-24<p<10-8). While IKZF1 results are also well-supported in non-Asian populations, due to poor SNP coverage, European-GWAS identified IKZF2 (1.2x10-13) could not be thoroughly assessed in our study. However, our bioinformatics data predicted several IKZF1-2 variants as eQTLs, again indicating their regulatory roles in expression. Despite solid evidence of association, a gap exists in defining mechanisms with IKZF1-2 variants, hence, the functional effects of IKZF1-2 risk alleles in SLE remains largely unaddressed. Since SLE is 3-5 times more prevalent in individuals of non-European ancestry, a comprehensive, sequence-based trans-ethnic mapping (TEM) approach will be informative to both identify additional causal variants, and understand SLE clinical heterogeneity across ethnicities. We have successfully applied TEM in SLE, and our research team has the expertise, resources and infrastructure necessary to move beyond GWAS and accelerate discovery and analysis of functional variants. We successfully identified causal variants and their functional consequences in ITGAM, BLK, IFIH1 and NCF2. We will apply our expertise in new variant discovery, localizing functional variants, and correlation of functional risk variants in IKZF1-2 on cellular and molecular surrogates associated with SLE. In Aim 1, we will localize additional SLE-predisposing variants from IKZF1-2 by performing comprehensive trans-ethnic mapping across four ethnically diverse populations (N>20,000 from Asian, African-American, European-American, and Hispanic descent). Promising variants, especially imputed and low frequency variants, will be validated by confirmatory genotyping. We will also correlate genetic and clinical heterogeneity using clinical sub-phenotypes and autoantibody profiles. In Aim 2, we will use cutting-edge approaches to directly identify functional variants in the enhancers of IKZF1-2 important for regulating expression using a novel allele-specific reporter system which works in the native chromatin context and in relevant cell types. This enables direct experimental validation of the most important variants in a human model cell system. Data generated will provide answers about SLE disease mechanisms influenced by IKZF1-2 variants, and the understanding of function of molecular variants on regulation of this pathway may enable precision application of existing treatments targeting this pathway and elucidate of new targets without the serious adverse events and limitations of these current thalidomide family-based therapies.

项目概要系统性红斑狼疮 (SLE) 是一种复杂的自身免疫性疾病，具有很大的遗传因素。最近的全基因组关联研究 (GWAS) 已经确定了 SLE 相关位点，包括 IKZF1 和 IKZF2，分别编码 ikaros 和 helios 蛋白。这些蛋白质在调节中发挥重要作用免疫细胞的分化对于系统性红斑狼疮的发展很重要，而调节这些蛋白质水平的药物是用于治疗难治性皮肤狼疮和肾炎，有力地证明了这些基因的重要性在系统性红斑狼疮中。我们最近在亚洲人中进行的基于免疫芯片的关联研究牢固地确立了 IKZF1-SLE 关联并检测到其他独立变异 (10-24<p<10-8)。虽然 IKZF1 结果也得到了很好的支持非亚洲人群，由于 SNP 覆盖率较差，欧洲 GWAS 无法识别 IKZF2 (1.2x10-13) 在我们的研究中进行了彻底的评估。然而，我们的生物信息学数据预测了几个 IKZF1-2 变异： eQTL，再次表明它们在表达中的调节作用。尽管有确凿的关联证据，但仍存在差距定义 IKZF1-2 变异的机制，因此，IKZF1-2 风险等位基因在 SLE 中的功能作用很大程度上仍未得到解决。由于 SLE 在非欧洲血统的个体中的患病率是其 3-5 倍，全面的、基于序列的跨种族绘图（TEM）方法将为识别其他因果变异，并了解跨种族的 SLE 临床异质性。我们已经成功在 SLE 中应用 TEM，我们的研究团队拥有移动所需的专业知识、资源和基础设施超越 GWAS 并加速功能变异的发现和分析。我们成功找出了因果关系 ITGAM、BLK、IFIH1 和 NCF2 中的变体及其功能后果。我们将运用我们的专业知识 IKZF1-2 中新变异的发现、功能变异的定位以及功能风险变异的相关性与 SLE 相关的细胞和分子替代物。在目标 1 中，我们将定位其他 SLE 易感因素 IKZF1-2 的变体，通过在四个不同种族之间进行全面的跨种族绘图人口（N>20,000，来自亚洲、非洲裔美国人、欧洲裔美国人和西班牙裔美国人）。有前途变异，特别是估算变异和低频变异，将通过确认性基因分型进行验证。我们将还使用临床亚表型和自身抗体谱将遗传和临床异质性关联起来。在目标2，我们将使用尖端方法直接识别IKZF1-2增强子中的功能变异对于使用在本地工作的新型等位基因特异性报告系统调节表达非常重要染色质背景和相关细胞类型。这使得最重要的直接实验验证成为可能人类模型细胞系统中的变异。生成的数据将提供有关 SLE 疾病机制的答案受 IKZF1-2 变体的影响，以及对分子变体对其调节的功能的理解途径可能能够精确应用针对该途径的现有治疗方法并阐明新的治疗方法目标没有严重的不良事件和这些当前沙利度胺系列疗法的局限性。