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: 9053279
• 负责人: Swapan K. Nath
• 金额: $ 42.88万
• 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/9053279
• 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 Methylation; 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; ITGAM gene; Individual; Intercistronic Region; Introns; Kidney; Linkage Disequilibrium; Lupus; Lupus Nephritis; Medical Genetics; 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; Susceptibility Gene; System; Systemic Lupus Erythematosus; Therapeutic Intervention; Tissues; Variant; Woman; base; clinical sequencing; cohort; curative treatments; database of Genotypes and Phenotypes; deep sequencing; ds-DNA; ethnic minority population; exome sequencing; experience; genetic association; genome wide association study; health disparity; histone methylation; molecular modeling; mortality; novel; research study; targeted sequencing; 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）：系统性红斑狼疮（SLE或狼疮）是一种多系统、临床异质性的自身免疫性疾病，具有丰富的遗传基础。SLE不成比例地影响女性（90%）和少数民族，如非洲裔美国人（AA）。与欧美人（EA）相比，AA患病率高3-5倍，临床表现和器官损害更严重，尤其是肾脏（狼疮性肾炎）。种族间的遗传变异可以解释疾病严重程度和临床表现的潜在差异。然而，狼疮的遗传结构，特别是AA，在很大程度上是未知的。虽然最近对欧洲和亚洲祖先的全基因组关联研究（GWAS）发现了40多个易感位点，但这些研究都没有集中在AA中验证这些关联的稳健性或发现新的信号。此外，由于大多数相关变异位于内含子或基因内区域，GWAS不能成功地精确定位实际的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，很难预测功能性后果