NADPH-Oxidase and SLE Susceptibility

NADPH 氧化酶和 SLE 易感性

基本信息

批准号：
8651414
负责人：
Swapan K. Nath
金额：
$ 21万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651414
关键词：
Accounting Affect African African American American Asians Autoantibodies Autoimmune Diseases Autophagocytosis Bacterial Infections Binding Biocompatible Materials Bioinformatics Biological Candidate Disease Gene Caucasians Caucasoid Race Cell membrane Cessation of life Chronic Clinical Communities Complex Computer Simulation Data Development Disease Early Diagnosis Essential Genes Ethnic Origin European Face Family Functional disorder Future Gene Family Genes Genetic Genotype Goals Grant Heterogeneity Hispanics Hydrogen Peroxide ITGAM gene Immune Immunity Individual Infection Infectious Agent Inflammation Inflammatory Invaded Koreans Lupus Lupus Nephritis Maps Mediating Methods Molecular Molecular Models Morbidity - disease rate Mycoses NADP NADPH Oxidase Native Americans Odds Ratio Organ Oxidases Pathogenesis Patients Phagocytosis Phenotype Physiological Population Control Population Heterogeneity Predisposition Prevalence Process Production Proteins Public Health Reaction Reactive Oxygen Species Records Recurrence Regulation Relative (related person)Research Research Design Research Infrastructure Resources Role Signal Transduction Structure Superoxides Susceptibility Gene System Systemic Lupus Erythematosus Therapeutic Intervention Time Transcriptional Regulation United States Variant Vertebrates Woman base cohort congenital immunodeficiency diagnosis design experience follow-up genetic variant genome database genome wide association study global health human CYBA protein immune activation immunoregulation male microbial molecular modeling monocyte mortality neutrophil neutrophil cytosol factor 40K neutrophil cytosol factor 67K novel pathogen protein complex public health relevance rare variant research study success systemic autoimmune disease

项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE or lupus) is a complex, multi-organ, clinically heterogeneous, potentially fatal autoimmune disease with substantial genetic and environmental components. In U.S., SLE affects ~2 million people, mostly women (~90%), and prevalence is >3-5 times higher in individuals of African, Asian and Hispanic ancestries compared to European ancestry. Despite its public health importance, SLE pathogenesis is not well understood. Infection is a leading cause of morbidity and mortality, accounting for >25% of deaths in SLE patients. Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide are key for defense against invading microbial pathogens, and are produced by the multi-protein NADPH- oxidase (NADPHO) system during phagocytosis. This multi-protein complex is encoded by 7 essential genes: NCF1, NCF2, NCF4, CYBA,CYBB, Rac1 or Rac2. Although NADPHO is likely to be important in SLE pathophysiology, thus far, none of the 7 genome-wide association studies detected SLE association. Using large multi-ethnic cohorts (N > 17,000 from European-Americans (EA), African-Americans (AA), Hispanics (HS), and Koreans (KR)), we have identified at least 7 independent and potentially functional SLE-susceptibility variants (10-44<p<10-7) within NCF2. We also have suggestive evidence (10-4<p<10-2) of multiple variants from genes encoding the other subunits of NADPHO, implicating its causal role in SLE susceptibility. We identified both ethnically-robust and ethnicity-specific SLE predisposing variants. Moreover, our data suggest that variation in NADPHO may influence SLE clinical sub-phenotypes; i.e., in EA, missense rs17849502 is more strongly associated with lupus nephritis (odds ratio (OR) = 3.5), and with SLE in males (OR = 4.23), compared to SLE in general (OR = 2.5). Follow up bioinformatic and molecular modeling analyses on selected variants show high conservation across vertebrates, implicating potential functional roles and predicting detrimental effects on NADPHO assembly that ultimately disrupt ROS production. We hypothesize that dense genotyping using individuals from 4 ethnically diverse populations, combined with conditional analysis and molecular modeling, will identify multiple potentially functional variants (rare and common), both ethnically robust and ethnicity-specific, within NADPHO genes. We propose three Specific Aims: (1) Identify and pinpoint SLE- predisposing variants within genes encoding the NADPHO complex, (2) Elucidate genetic variants contributing to the clinical heterogeneity of SLE, (3) Use these in conjunction with molecular modeling to predict mechanistic effects of SLE-predisposing functional variants. With our preliminary findings, research strategies, available biomaterials, resources, infrastructure, and experience, expertise and track records of our research team, we have excellent potential to successfully complete the proposed project. Ultimately, a set of novel functional variants will be made available to the scientific community and provide a basis for future biological experiments to define how NADPHO contributes to the pathological mechanisms of lupus.

描述（由申请人提供）：系统性红斑狼疮（SLE 或狼疮）是一种复杂的、多器官的、临床异质性的、潜在致命的自身免疫性疾病，具有大量的遗传和环境因素。在美国，SLE 影响约 200 万人，其中大多数是女性 (约 90%)，非洲、亚洲和西班牙裔人群的患病率是欧洲裔人群的 3-5 倍以上。尽管系统性红斑狼疮对公共卫生具有重要意义，但其发病机制尚不清楚。感染是发病和死亡的主要原因，占 SLE 患者死亡人数的 25% 以上。活性氧 (ROS)，例如超氧化物和过氧化氢，是防御微生物病原体入侵的关键，由多蛋白 NADPH 氧化酶 (NADPHO) 系统在吞噬过程中产生。这种多蛋白复合物由 7 个必需基因编码：NCF1、NCF2、NCF4、CYBA、CYBB、Rac1 或 Rac2。尽管 NADPHO 可能在 SLE 病理生理学中很重要，但迄今为止，7 项全基因组关联研究均未检测到 SLE 关联。使用大型多种族队列（N > 17,000，来自欧洲裔美国人 (EA)、非裔美国人 (AA)、西班牙裔 (HS) 和韩国人 (KR)），我们已经确定了至少 7 种独立且潜在的功能性 SLE 易感性NCF2 内的变体 (10-44<p<10-7)。我们还获得了来自编码 NADPHO 其他亚基的基因的多种变异的提示性证据 (10-4<p<10-2)，暗示其在 SLE 易感性中的因果作用。我们发现了种族稳健性和种族特异性 SLE 易感变异。此外，我们的数据表明 NADPHO 的变异可能影响 SLE 临床亚型；即，在 EA 中，与一般 SLE (OR = 2.5) 相比，错义 rs17849502 与狼疮性肾炎 (OR = 3.5) 以及男性 SLE (OR = 4.23) 的相关性更强。对选定变体的后续生物信息学和分子模型分析显示，脊椎动物之间具有高度保守性，这暗示了潜在的功能作用，并预测对 NADPHO 组装的有害影响，最终破坏 ROS 的产生。我们假设，使用来自 4 个不同种族人群的个体进行密集基因分型，结合条件分析和分子建模，将识别多种潜在的功能变异（罕见和常见），无论是种族上的还是变异的。 NADPHO 基因内具有强大且种族特异性。我们提出了三个具体目标：(1) 识别并查明编码 NADPHO 复合物的基因内诱发 SLE 的变异，(2) 阐明导致 SLE 临床异质性的遗传变异，(3) 将这些变异与分子模型结合使用来预测机制诱发 SLE 的功能变异的影响。凭借我们的初步发现、研究策略、可用的生物材料、资源、基础设施以及研究团队的经验、专业知识和跟踪记录，我们拥有成功完成拟议项目的巨大潜力。最终，一组新的功能变异将提供给科学界，并为未来的生物学实验提供基础，以定义 NADPHO 如何促进狼疮的病理机制。