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

• 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
• 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

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.

项目摘要 系统性红斑狼疮(SLE)是一种复杂的自身免疫性疾病，具有重要的遗传成分。 最近的全基因组关联研究已经确定了SLE相关基因座，包括IKZF1和 IKZF2，分别编码Ikaros和Helios蛋白。这些蛋白在细胞周期调控中发挥着重要作用。 免疫细胞的分化对系统性红斑狼疮的发展和调节这些蛋白质水平的药物是重要的 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。我们最近在亚洲人中基于免疫芯片的关联研究坚定地确立了IKZF1-SLE的关联 并检测到其他独立变异体(10-24&lt；p&lt；10-8)。虽然IKZF1的结果也得到了 非亚洲人群，由于SNP覆盖率较低，欧洲-GWAS鉴定的IKZF2(1.2x10-13)不能 在我们的研究中得到了彻底的评估。然而，我们的生物信息学数据预测，几个IKZF1-2变体为 EQTL，再次表明它们在表达中的调节作用。尽管有确凿的证据表明两者之间存在关联，但仍存在差距 因此，在定义IKZF1-2变异的机制时，IKZF1-2风险等位基因在SLE中的功能效应 在很大程度上仍然没有得到解决。由于系统性红斑狼疮在非欧洲血统的个体中的患病率是普通人的3-5倍， 一种全面的、基于序列的跨种族映射(TEM)方法将为识别两者提供信息 更多的因果变异，并了解SLE临床跨种族的异质性。我们已经成功地 将透射电子显微镜应用于SLE，我们的研究团队拥有必要的专业知识、资源和基础设施 并加速功能变异的发现和分析。我们成功地找出了原因 ITGAM、BLK、IFIH1和NCF2中的变体及其功能后果。我们将把我们的专业知识应用于 IKZF1-2中新的变异发现、功能变异的定位和功能风险变异的相关性 与系统性红斑狼疮相关的细胞和分子替代物。在目标1中，我们将本地化其他易患系统性红斑狼疮 通过在四个不同种族之间执行全面的跨种族映射来实现IKZF1-2的变体 人口(N&GT；20,000名亚裔、非洲裔、欧洲裔美国人和西班牙裔美国人)。前景看好 变种，特别是归因型和低频变种，将通过确认性基因分型进行验证。我们会 还使用临床亚型和自身抗体图谱将遗传和临床异质性联系起来。在……里面 目标2，我们将使用尖端方法直接鉴定IKZF1-2增强子中的功能变体 对于使用一种新的等位基因特异性报告系统调节表达很重要，这种报告系统在原生生物中有效 染色质背景和相关细胞类型。这使得能够直接通过实验验证最重要的 人体模型细胞系统中的变种。生成的数据将提供关于SLE疾病机制的答案 受IKZF1-2突变体的影响及对分子突变体调控功能的认识 途径可以实现针对该途径的现有治疗的精确应用，并阐明新的 没有目前这些基于沙利度胺的家庭疗法的严重不良事件和限制的目标。