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Role of Two Interferon Regulatory Genes in Lupus

两个干扰素调节基因在狼疮中的作用

基本信息

批准号：
9895394
负责人：
Swapan K. Nath
金额：
$ 21.85万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895394
关键词：
African American Alleles American Antigen-Antibody Complex Asian Americans Asians Autoantibodies Autoimmune Diseases Autoimmunity Base Sequence Binding Bioinformatics Blood Blood Cells Candidate Disease Gene Caucasians Cell Line Cells Chromatin Clinical Complex Cultured Cells Data Dendritic Cells Deposition Development Diagnosis Disease Drug Targeting Epigenetic Process Ethnic Origin European Family Frequencies Future Gene Expression Genes Genetic Genetic Heterogeneity Genotype Goals Haplotypes Heritability Hispanics Histidine Host Defense Human Hyperactive behavior Immune Immune response Immune system In Vitro Incidence Individual Infection Inflammation Inflammatory Interferon Type I Interferon Type II Interferon-alpha Interferons Interleukin-12 Kidney Knock-out Lead Link Linkage Disequilibrium Luciferases Lupus Lupus Nephritis Malignant Neoplasms Mediating Molecular Mus Mutation Organ Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Plant Roots Play Population Population Heterogeneity Predisposition Prevention strategy Production Records Regulator Genes Reporting Research Resources Risk Risk Factors Role Running Sampling Serum Spleen Structure System Systemic Lupus Erythematosus Tissues Validation Variant Woman base causal variant clinical heterogeneity cytokine early onset ethnic disparity ethnic diversity experimental study genetic association genetic signature genetic variant genome wide association study insight lymph nodes macrophage men monocyte mouse model mutant new therapeutic target novel novel therapeutics peripheral lymphoid organ prototype risk variant solute therapeutic target

项目摘要

ABSTRACT Systemic lupus erythematosus (SLE or lupus) is a prototype of type-I interferon (IFN-I)-mediated autoimmune disease, characterized by a myriad of clinical manifestations including inflammation, pathogenic autoantibody production, and irreversible end-organ damage (e.g. kidneys). SLE disproportionately afflicts women (nine-fold higher than men) and non-white ethnicities. Asians and African-Americans have higher SLE incidence, more severe disease manifestations, and greater risk of organ damage (e.g. lupus nephritis) than Caucasians. Others and we have reported that several IFN regulatory genes, including IFN regulatory factor 8 (IRF8), and solute carrier family 15 number 4 (SLC15A4) are involved in SLE susceptibility. IFNs are a family of cytokines with important roles in infection, cancer, and autoimmunity. In vitro evidence suggests that plasmacytoid dendritic cells (pDCs), the principal IFN-I producing immune cells, are intimately involved in SLE development. A recent study using two mouse models (Irf8-/- knockout and Slc15a4 mutant) provided direct evidence that pDCs contribute to SLE via hyper-production of IFN-I. Thus, IRF8 and SLC15A4 could potentially be involved in human SLE progression. Our genetic association data identified several potential SLE predisposing variants for IRF8 (best p=1.2x10-22) and for SLC15A4 (best p=1.5x10-21) across multiple ethnicities. However, despite strong association, specific pathogenic variants and their underlying molecular mechanisms are not yet defined. Using bioinformatics, we predicted that several associated variants are cis-eQTLs, with roles in regulating gene expression. Using luciferase and ChIP-qPCR, we experimentally validated allele-specific effects of several predicted functional variants. Since IFN gene signatures are a prominent feature in SLE, we hypothesize that comprehensive, trans-ethnic mapping (TEM) followed by experimental validation with functional genetics, including genetic and epigenetic editing in relevant immune cells, will identify causal variants and their functional consequences in IFN-I production. Our research team has the expertise, resources, and track records to discover and characterize functional variants for SLE. In Aim 1, we will localize SLE-predisposing variants from these genes by performing comprehensive imputation-based TEM across ethnically diverse populations (N>30,000 from Asians, African-Americans, European-Americans, Egyptians, and Hispanics). Promising variants, especially imputed and low-frequency variants, will be validated through additional confirmatory genotyping. We will elucidate genetic and clinical heterogeneity by assessing associations with clinical sub-phenotypes and autoantibodies. In Aim 2, we will experimentally validate functional relevance of putative variants as regulators of gene expression and IFN-I production. We will use both cultured cells (THP-1) and primary immune cells (pDCs, monocytes) from SLE patients and controls. Insights gained from this project will help to define the molecular mechanisms underlying how risk alleles predispose to SLE, and may define novel drug/therapeutic targets for SLE in the future.

摘要系统性红斑狼疮（SLE或狼疮）是I型干扰素（IFN-I）介导的自身免疫的原型疾病，其特征在于包括炎症、致病性自身抗体生产和不可逆的终末器官损伤（如肾脏）。SLE不成比例地折磨女性（九倍于高于男性）和非白人种族。亚裔和非裔美国人SLE发病率较高，严重的疾病表现，器官损伤（如狼疮性肾炎）的风险高于白人。别人我们已经报道了几个IFN调节基因，包括IFN调节因子8（IRF 8）和溶质，携带者家族15号4（SLC 15 A4）参与SLE易感性。IFN是细胞因子家族，在感染、癌症和自身免疫中发挥重要作用。体外研究表明，浆细胞样树突状细胞细胞（pDC），主要的产生IFN-1的免疫细胞，密切参与SLE的发展。最近的一使用两种小鼠模型（Irf 8-/-敲除和Slc 15 a4突变体）的研究提供了pDC 通过IFN-1的过度产生而导致SLE。因此，IRF 8和SLC 15 A4可能参与了人类的免疫调节。 SLE进展。我们的遗传关联数据确定了IRF 8的几个潜在SLE易感变异体 (best p=1.2x10-22）和SLC 15 A4（最佳p=1.5x10-21）。然而，尽管强劲相关性，具体的致病性变体及其潜在的分子机制尚未确定。使用通过生物信息学分析，我们预测了几个相关的变异体是cis-eQTL，它们在基因调控中起作用，表情使用荧光素酶和ChIP-qPCR，我们通过实验验证了几个基因的等位基因特异性效应。预测的功能变体。由于IFN基因特征是SLE的显著特征，我们假设，全面的跨种族绘图（TEM），然后通过功能遗传学进行实验验证，包括相关免疫细胞中的遗传和表观遗传编辑，将识别因果变异及其功能 IFN-I生产的影响。我们的研究团队拥有专业知识、资源和跟踪记录，并表征SLE的功能变体。在目标1中，我们将从这些地方化SLE易感变体，通过在不同种族的人群中进行基于综合插补的TEM（N> 30，000 来自亚洲人、非洲裔美国人、欧洲裔美国人、埃及人和西班牙裔美国人）。有前途的变种，特别是插补和低频变异，将通过额外的确证性基因分型进行验证。我们将通过评估与临床亚表型的关联来阐明遗传和临床异质性，自身抗体在目标2中，我们将通过实验验证推定变体作为调节剂的功能相关性基因表达和IFN-I的产生。我们将使用培养的细胞（THP-1）和原代免疫细胞 (pDCs单核细胞）。从这个项目中获得的见解将有助于确定潜在的分子机制如何风险等位基因易感SLE，并可能定义新的药物/治疗 SLE的未来目标。