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:
- 金额:$ 21万
- 依托单位:
- 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:
- 关键词:AccountingAffectAfricanAfrican AmericanAmericanAsiansAutoantibodiesAutoimmune DiseasesAutophagocytosisBacterial InfectionsBindingBiocompatible MaterialsBioinformaticsBiologicalCandidate Disease GeneCaucasiansCaucasoid RaceCell membraneCessation of lifeChronicClinicalCommunitiesComplexComputer SimulationDataDevelopmentDiseaseEarly DiagnosisEssential GenesEthnic OriginEuropeanFaceFamilyFunctional disorderFutureGene FamilyGenesGeneticGenotypeGoalsGrantHeterogeneityHispanicsHydrogen PeroxideITGAM geneImmuneImmunityIndividualInfectionInfectious AgentInflammationInflammatoryInvadedKoreansLupusLupus NephritisMapsMediatingMethodsMolecularMolecular ModelsMorbidity - disease rateMycosesNADPNADPH OxidaseNative AmericansOdds RatioOrganOxidasesPathogenesisPatientsPhagocytosisPhenotypePhysiologicalPopulation ControlPopulation HeterogeneityPredispositionPrevalenceProcessProductionProteinsPublic HealthReactionReactive Oxygen SpeciesRecordsRecurrenceRegulationRelative (related person)ResearchResearch DesignResearch InfrastructureResourcesRoleSignal TransductionStructureSuperoxidesSusceptibility GeneSystemSystemic Lupus ErythematosusTherapeutic InterventionTimeTranscriptional RegulationUnited StatesVariantVertebratesWomanbasecohortcongenital immunodeficiencydiagnosis designexperiencefollow-upgenetic variantgenome databasegenome wide association studyglobal healthhuman CYBA proteinimmune activationimmunoregulationmalemicrobialmolecular modelingmonocytemortalityneutrophilneutrophil cytosol factor 40Kneutrophil cytosol factor 67Knovelpathogenprotein complexpublic health relevancerare variantresearch studysuccesssystemic 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成分。在美国,SLE影响约200万人,大多数是女性(约90%),非洲、亚洲和西班牙血统个体的患病率是欧洲血统个体的3-5倍。尽管其对公共卫生的重要性,但SLE的发病机制尚未得到很好的理解。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),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(NADPH)系统产生。这种多蛋白复合物由7个必需基因编码:NCF 1,NCF 2,NCF 4,CYBA,CYBB,Rac 1或Rac 2。尽管NADPH可能在SLE病理生理学中很重要,但到目前为止,7项全基因组关联研究均未发现SLE相关性。使用大型多种族队列(来自欧洲裔美国人(EA),非洲裔美国人(AA),西班牙裔美国人(HS)和韩国人(KR)的N > 17,000),我们已经在NCF 2中确定了至少7个独立的和潜在功能性SLE易感性变体(10-44<p<10-7)。我们也有提示性的证据(10-4<p<10-2),来自编码NADPH其他亚基的基因的多个变体,暗示其在SLE易感性中的因果作用。我们确定了种族稳健和种族特异性SLE易感变异。此外,我们的数据表明,NADPH的变化可能会影响SLE临床亚表型;即,在EA中,错义rs 17849502与狼疮性肾炎(优势比(OR)= 3.5)和男性SLE(OR = 4.23)的相关性更强(OR = 2.5)。对选定变体的后续生物信息学和分子建模分析显示脊椎动物之间的高度保守性,暗示潜在的功能作用,并预测对最终破坏ROS产生的NADPH组装的有害影响。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性变体(罕见和常见),无论是在种族上
在NADPH基因中具有强大的种族特异性。我们提出了三个具体目标:(1)识别和精确定位编码NADPH复合物的基因内的SLE易感变异体,(2)阐明导致SLE临床异质性的遗传变异体,(3)将这些与分子建模结合使用,以预测SLE易感功能变异体的机制效应。凭借我们的初步发现,研究策略,可用的生物材料,资源,基础设施以及我们研究团队的经验,专业知识和跟踪记录,我们有很好的潜力成功完成拟议的项目。最终,一组新的功能变体将提供给科学界,并为未来的生物学实验提供基础,以确定NADPH如何促进狼疮的病理机制。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Oxidative stress and its biomarkers in systemic lupus erythematosus.
- DOI:10.1186/1423-0127-21-23
- 发表时间:2014-03-17
- 期刊:
- 影响因子:11
- 作者:Shah D;Mahajan N;Sah S;Nath SK;Paudyal B
- 通讯作者:Paudyal B
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Swapan K. Nath其他文献
Genetic epidemiology of vitiligo: multilocus recessivity cross-validated.
白癜风的遗传流行病学:多位点隐性交叉验证。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:9.8
- 作者:
Swapan K. Nath;Partha P. Majumder;James J. Nordlund - 通讯作者:
James J. Nordlund
potential for generating B cells with a diverse immunoglobulin repertoire Human fetal, cord blood, and adult lymphocyte progenitors have similar
产生具有多种免疫球蛋白库的 B 细胞的潜力 人类胎儿、脐带血和成人淋巴细胞祖细胞具有相似的特性
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
Grant R. Kolar;Takafumi Yokota;Maria Isabel D. Rossi;Swapan K. Nath;J. D. Capra - 通讯作者:
J. D. Capra
Swapan K. Nath的其他文献
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{{ truncateString('Swapan K. Nath', 18)}}的其他基金
Contributions of autophagy-related genes in lupus
自噬相关基因在狼疮中的贡献
- 批准号:
10682136 - 财政年份:2023
- 资助金额:
$ 21万 - 项目类别:
Connecting the gap between GWAS and functional targets for lupus susceptibility
连接 GWAS 和狼疮易感性功能目标之间的差距
- 批准号:
10618360 - 财政年份:2022
- 资助金额:
$ 21万 - 项目类别:
Connecting the gap between GWAS and functional targets for lupus susceptibility
连接 GWAS 和狼疮易感性功能目标之间的差距
- 批准号:
10433444 - 财政年份:2022
- 资助金额:
$ 21万 - 项目类别:
Role of Two Interferon Regulatory Genes in Lupus
两个干扰素调节基因在狼疮中的作用
- 批准号:
9895394 - 财政年份:2020
- 资助金额:
$ 21万 - 项目类别:
Role of Two Interferon Regulatory Genes in Lupus
两个干扰素调节基因在狼疮中的作用
- 批准号:
10115587 - 财政年份:2020
- 资助金额:
$ 21万 - 项目类别:
Localizing functional variants in SLE susceptibility genes
定位 SLE 易感基因的功能变异
- 批准号:
8995183 - 财政年份:2015
- 资助金额:
$ 21万 - 项目类别:
Localizing functional variants in SLE susceptibility genes
定位 SLE 易感基因的功能变异
- 批准号:
8823171 - 财政年份:2015
- 资助金额:
$ 21万 - 项目类别:
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:
9259737 - 财政年份:2014
- 资助金额:
$ 21万 - 项目类别:
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 - 财政年份:2014
- 资助金额:
$ 21万 - 项目类别:
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 - 财政年份:2014
- 资助金额:
$ 21万 - 项目类别:
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