Health Disparities and Genetic Architecture of Lupus in African Americans

非裔美国人的健康差异和狼疮的遗传结构

基本信息

批准号：
8776043
负责人：
Swapan K. Nath
金额：
$ 42.75万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-10 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8776043
关键词：
Accounting Affect African American Age Age of Onset Alleles American Antigen-Antibody Complex Architecture Asians Autoantibodies Autoimmune Diseases Bioinformatics Biological Blood Candidate Disease Gene Chromatin Chronic Clinical Complement Activation Controlled Study DNA DNA Resequencing Data Deposition Diagnosis Disease Enhancers Epigenetic Process Ethnic Origin Ethnic group Etiology European Experimental Designs Face Future Gene Frequency Gene Targeting Genes Genetic Genetic Variation Genome Genotype Health Heterogeneity High Prevalence Histones ITGAM gene Individual Intercistronic Region Introns Kidney Linkage Disequilibrium Lupus Lupus Nephritis Methylation Molecular Molecular Models Morbidity - disease rate Organ Pathogenesis Patients Phenotype Population Predisposition Prevalence Process Production Research Research Infrastructure Resources Sampling Severity of illness Signal Transduction System Systemic Lupus Erythematosus Therapeutic Intervention Tissues Variant Woman base cohort database of Genotypes and Phenotypes deep sequencing ethnic minority population exome sequencing experience genetic association genome wide association study health disparity molecular modeling mortality novel public health relevance research study theories therapy development

项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE or lupus) is a multi-system, clinically heterogeneous autoimmune disease with substantial genetic basis. SLE disproportionately affects women (90%) and ethnic minorities like African- Americans (AA). Compared to European-Americans (EA), AA show 3-5 fold higher prevalence and have more severe clinical manifestations and organ damage, especially kidneys (lupus nephritis). Genetic variation between ethnicities could account for underlying differences in disease severity and clinical manifestations. However, the genetic architecture of lupus, especially in AA, is largely unknown. While recent genome-wide association studies (GWAS) on European and Asian ancestries identified over 40 susceptibility loci, none of these were focused in AA to verify the robustness of these association or identify novel signals. Additionally, since the majority of associated variants are located in introns or intragenic regions, GWAS is not successful for pinpointing actual predisposing variants or providing the full allelic spectrum of causal variants underlying these association signals. Therefore, it is difficult to predict functional consequences of genetic association. This poor understanding of underlying biological mechanisms hinders improvements in the diagnosis and treatment for SLE. Our research team has acquired experience, expertise, resources, and infrastructure necessary to move beyond GWAS to accelerate the discovery and characterization of causal variants underlying GWAS signals. We have successfully identified functional SLE predisposing variants in ITGAM, IFIH1 and NCF2, and propose extending this discovery effort to other candidate genes in AA. This is an essential prerequisite to understanding disease disparities in SLE. Our experimental design incorporates data from genetics (including sequencing), clinical sub-phenotypes and autoantibodies, eQTLs, and ENCODE (annotation of enhancers, chromatin states, DNA and histone methylation, etc.), followed by bioinformatics and molecular modeling for understanding the mechanistic effects to predict functional SNPs. Aim 1 is to perform targeted deep-sequencing on >1500 AA samples to thoroughly assess 25 strongly associated (10-24<p<10-6) signals. Aim 2 is to conduct imputation-based association analysis using out-of-study controls (dbGaP) (>18,000) in order to maximize power to detect associated variants, and confirm these associations in >4000 AA samples. Our proposed cohort has adequate power to detect both rare and common variants. Aim 3 is to elucidate genetic and clinical heterogeneity of SLE by assessing association between predisposing variants and SLE clinical sub-phenotypes (e.g., lupus nephritis) and autoantibodies. Aim 4 is to predict mechanistic effects of SLE-predisposing variants using bioinformatics analysis and molecular modeling. Ultimately, this project will yield a set of SLE associated functional variants in AA, providing the basis for in-depth biological experiments to define the pathological mechanisms, and define genetic architecture to uncover underlying health disparities. This may define novel targets and guide options for future therapeutic interventions.

描述（由申请人提供）：系统性红斑狼疮（SLE 或狼疮）是一种多系统、临床异质性自身免疫性疾病，具有显着的遗传基础。 SLE 不成比例地影响女性 (90%) 和非洲裔美国人 (AA) 等少数族裔。与欧美人 (EA) 相比，AA 的患病率高出 3-5 倍，且临床表现和器官损害更严重，尤其是肾脏（狼疮性肾炎）。种族之间的遗传变异可以解释疾病严重程度和临床表现的根本差异。然而，狼疮的遗传结构，尤其是 AA 的遗传结构，在很大程度上尚不清楚。虽然最近针对欧洲和亚洲血统的全基因组关联研究 (GWAS) 确定了 40 多个易感位点，但这些基因座都没有集中于 AA 来验证这些关联的稳健性或识别新信号。此外，由于大多数相关变异位于内含子或基因内区域，GWAS 无法成功查明实际易感变异或提供这些关联信号背后的因果变异的完整等位基因谱。因此，很难预测功能后果的遗传关联。对潜在生物学机制的了解不足阻碍了 SLE 诊断和治疗的改进。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 GWAS 信号背后因果变异的发现和表征。我们已经成功鉴定了 ITGAM、IFIH1 和 NCF2 中的功能性 SLE 易感变异，并建议将这一发现工作扩展到 AA 中的其他候选基因。这是了解 SLE 疾病差异的重要先决条件。我们的实验设计结合了来自遗传学（包括测序）、临床亚表型和自身抗体、eQTL 和 ENCODE（增强子注释、染色质状态、DNA 和组蛋白甲基化等）的数据，然后通过生物信息学和分子建模来了解机制预测功能性 SNP 的效果。目标 1 是对 >1500 个 AA 样本进行靶向深度测序，以彻底评估 25 个强相关 (10-24<p<10-6) 信号。目标 2 是使用研究外对照 (dbGaP) (>18,000) 进行基于插补的关联分析，以最大限度地提高检测相关变异的能力，并在 >4000 个 AA 样本中确认这些关联。我们提出的队列有足够的能力来检测罕见和常见的变异。目标 3 是通过评估易感变异与 SLE 临床亚型（例如狼疮性肾炎）和自身抗体之间的关联来阐明 SLE 的遗传和临床异质性。目标 4 是利用生物信息学分析和分子建模来预测 SLE 易感变异的机制效应。最终，该项目将产生一组与 SLE 相关的 AA 功能变异，为深入的生物学实验提供基础，以定义病理机制，并定义遗传结构以揭示潜在的健康差异。这可能会定义新的目标并指导未来治疗干预的选择。