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：
9770772
负责人：
Joel Marvin Guthridge
金额：
$ 82.71万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9770772
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 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 early onset ethnic bias ethnic diversity experience experimental study follow-up genome wide association study human model induced pluripotent stem cell lupus cutaneous member molecular phenotype mortality novel risk variant 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.