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

• 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
• 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; 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

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）：全身性红斑狼疮（SLE或狼疮）是一种多系统的，临床上异质的自身免疫性疾病，具有可观的遗传基础。 SLE不成比例地影响妇女（90％）和少数民族（如非裔美国人）（AA）。与欧美人（EA）相比，AA的患病率高3-5，并且具有更严重的临床表现和器官损伤，尤其是肾脏（狼疮肾炎）。种族之间的遗传差异可以解释疾病严重程度和临床表现的潜在差异。但是，狼疮的遗传结构，尤其是在AA中，在很大程度上是未知的。尽管最近对欧洲和亚洲祖先的全基因组关联研究（GWAS）确定了40多个敏感性基因座，但这些研究均未集中在AA上以验证这些关联的鲁棒性或识别新型信号。此外，由于大多数相关的变体位于内含子或基因内区域，因此GWAS并未成功地指出实际的易感变体或提供这些关联信号上基于的因果变体的完整等位基因谱。因此，很难预测功能后果 遗传关联。对潜在生物学机制的这种不良理解阻碍了SLE诊断和治疗的改善。我们的研究团队已经获得了超越GWAS的经验，专业知识，资源和基础设施，以加速GWAS信号基础的因果变体的发现和表征。我们已经成功地识别了ITGAM，IFIH1和NCF2中的功能性SLE易感变体，并提出将这种发现工作扩展到AA中的其他候选基因。这是了解SLE中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），临床亚表征和自身抗体，EQTL和编码的数据（增强剂的注释，染色质状态，DNA和组蛋白甲基化等），然后是生物毒素和分子建模，以理解机械性效果。 AIM 1是对> 1500 AA样品进行有针对性的深入测量，以彻底评估25个密切相关的（10-24 <p <10-6）信号。 AIM 2是使用批准外控制（DBGAP）（> 18,000）进行基于估算的关联分析，以最大程度地发挥功能来检测相关变体，并在> 4000个AA样本中确认这些关联。我们提出的队列具有足够的能力来检测稀有和常见变体。 AIM 3是通过评估易感变体与SLE临床亚表格型（例如狼疮肾炎）和自身抗体之间的关联来阐明SLE的遗传和临床异质性。 AIM 4是使用生物信息学分析和分子建模来预测SLE-PREDISPODISPODISS变体的机理效应。最终，该项目将在AA中产生一组相关的功能变体，为深入的生物学实验提供了定义病理机制的基础，并定义遗传结构以发现潜在的健康差异。这可能定义了新的靶标和未来治疗干预措施的指导选择。