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）：全身性红斑狼疮（SLE或狼疮）是一种复杂的，多器官，临床上异质性的，潜在的致命自身免疫性疾病，具有实质性的遗传和环境成分。在美国，SLE影响了约200万人，大多数是妇女（约90％），而与欧洲血统相比，非洲，亚洲和西班牙裔祖先的人的患病率高于3-5倍。尽管公共健康的重要性，但SLE发病机理尚未得到充分理解。感染是发病率和死亡率的主要原因，占SLE患者死亡的25％。活性氧（ROS），例如超氧化物和过氧化氢是防御入侵微生物病原体的关键，并且在吞噬作用期间由多蛋白NADPH-氧化酶（NADPHO）系统产生。这种多蛋白质复合物由7个必需基因编码：NCF1，NCF2，NCF4，CYBA，CYBB，RAC1或RAC2。尽管NADPHO在SLE病理生理学中可能很重要，但到目前为止，尚未检测到SLE关联的7个基因组关联研究。我们使用大型多民族队列（n> 17,000名来自欧美人（EA），非裔美国人（AA），西班牙裔（HS）和韩国人（KR）（kr）），我们已经在NCF2内确定了至少7个独立且潜在的功能性SLE敏度变体（10-44 <p <10-7）。我们还提供了来自编码Nadpho其他亚基的基因的多种变体的暗示性证据（10-4 <p <10-2），这暗示了其在SLE易感性中的因果作用。我们确定了种族运动和种族特异性的SLE易感变体。此外，我们的数据表明，NADPHO的差异可能会影响SLE临床亚表格型。即，与SLE相比，在EA中，错过RS17849502与狼疮性肾炎（优势比（OR）= 3.5）和SLE（OR = 4.23）的相比（OR = 2.5）更加密切相关（OR = 4.23）。对选定变体的随访生物信息学和分子建模分析显示，跨脊椎动物的守恒较高，暗示了潜在的功能作用，并预测了最终破坏ROS产生的Nadpho组装的有害影响。我们假设使用来自4个种族多样性种群的个体，结合条件分析和分子建模的个体致密的基因分型将识别出多种潜在的功能变体（稀有和常见），这两者在种族上都是在纳德福基因内，强大的种族特异性。我们提出了三个特定的目的：（1）识别编码NADPHO复合物的基因中的SLE-SLE-诱发变异，（2）阐明有助于SLE的临床异质性的遗传变异，（3）与分子建模相结合的遗传异质性，以预测功能性变异的机械机械效应。借助我们的初步发现，研究策略，可用的生物材料，资源，基础设施以及经验，专业知识和跟踪我们的研究团队的记录，我们具有成功完成该项目的巨大潜力。最终，将为科学界提供一组新型的功能变体，并为将来的生物学实验提供基础，以定义Nadpho如何对狼疮的病理机制做出贡献。