Association of genetic and autoantibody signatures with SLE clinical course

遗传和自身抗体特征与 SLE 临床病程的关联

• 批准号: 8917092
• 负责人: Elizabeth E Brown
• 金额: $ 63.62万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-26 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8917092
• 关键词: Accounting; African; African American; Amerindian; Antibodies; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Biological Markers; Classification; Clinical; Clinical Data; Clinical Management; Collaborations; Complement Activation; Complex; DNA Sequence; Data; Disease; Environment; Environmental Risk Factor; Etiology; European; Expenditure; Genes; Genetic; Genomics; Genotype; Goals; Health; Healthcare; Human; Immune response; Immunoglobulin G; Immunoglobulin M; International; Investigation; Knowledge; Lead; Lupus; Lupus Nephritis; Maps; Microarray Analysis; Modeling; Molecular Abnormality; Monitor; Mutation; Nephritis; Organ; Outcome; Patients; Persons; Phenotype; Play; Population; Predisposition; Prevalence; Progressive Disease; Proxy; Relative (related person); Research; Resolution; Resources; Risk; Role; Serum; Severities; Specificity; Systemic Lupus Erythematosus; Technology; Testing; Therapeutic Intervention; Time; Variant; Vulnerable Populations; base; cohort; cost effective; design; endophenotype; ethnic minority population; genetic association; genetic profiling; genetic variant; genome-wide; high risk; high throughput technology; human genome sequencing; improved; indexing; innovation; insight; novel; prevent; prognostic; trait; trend

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that is characterized by the presence of antinuclear autoantibodies, complement activation and multisystem organ damage. Trends in SLE prevalence and clinical course differ by ancestry. The basis for this disparity remains poorly understood. Although the etiology of SLE is unclear, combinations of genetic and environmental factors play a causal role. The goal of the proposed investigation is to delineate the independent and combined effects of variation in DNA sequence with novel high resolution autoantibody profiles relative to the rate of progression and severity of lupus nephritis (LN) and severe organ damage among patients with SLE. We will test the overarching hypothesis that the genetic effect on extreme-trait SLE endophenotypes resulting from variation in multiple loci is stronger among persons with specific autoantibody profiles, which may account for the disparity observed among patients of African and Amerindian ancestry. To test this overarching hypothesis, we intend to determine the: (1) contribution of autoantibody specificity on the presence of and time to extreme-trait SLE endophenotypes, and differences by ancestry, using novel high resolution antigen microarrays, (2) contribution of variation in DNA sequence on the presence of and time to extreme-trait SLE endophenotypes using Illumina high throughput technologies and (3) extent to which variation in DNA sequence modifies the effect of autoantibody specificity on the presence, and time to, extreme- trait SLE endophenotypes. The proposed research is an innovative, timely and comprehensive strategy to identify novel genetic and serial autoantibody signature contributions to SLE clinical course. We will capitalize on a unique opportunity to explore cross-sectional and longitudinal outcomes with variation in DNA sequence and autoantibodies obtained from ethnically diverse, well-characterized population of SLE patients while taking advantage of recent technological advances in human genome sequencing and high resolution antigen microarray technologies. Within the scope of this proposal, we intend to leverage existing collaborations, resources and comprehensive, high quality, clinical data and genotyping collected in a well-characterized SLE inception cohort, to fill a critical gap in knowledge required to develop efforts to detect, prevent, manage and treat SLE. This approach offers the best opportunity to comprehensively characterize novel genetic and autoantibody relationships with SLE clinical course as a prognostic index for targeting high-risk vulnerable populations that may benefit from individualized clinical management or therapeutic intervention.

描述（由申请人提供）：全身性红斑狼疮（SLE）是一种原型自身免疫性疾病，其特征在于存在抗核自身抗体，补体激活和多系统器官损伤。 SLE患病率和临床过程的趋势因血统而异。这种差异的基础仍然很少理解。尽管SLE的病因尚不清楚，但遗传因素和环境因素的组合起着因果作用。拟议的研究的目的是与新型高分辨率自身抗体谱相对于狼疮肾炎的进展和严重程度（LN）和严重的器官损害的新型高分辨率自身抗体曲线描述DNA序列变异的独立和综合作用。我们将检验以下总体假设：在具有特定自身抗体概况的患者中，由于多个基因座的变化而导致的极端特征SLE内表型的遗传效应更强，这可能解释了非洲和美洲印第安人祖先患者之间观察到的差异。 To test this overarching hypothesis, we intend to determine the: (1) contribution of autoantibody specificity on the presence of and time to extreme-trait SLE endophenotypes, and differences by ancestry, using novel high resolution antigen microarrays, (2) contribution of variation in DNA sequence on the presence of and time to extreme-trait SLE endophenotypes using Illumina high throughput technologies and (3) extent to which DNA序列的变化改变了自身抗体特异性对存在的影响以及极端特征SLE内表型的影响。拟议的研究是一种创新，及时，全面的策略，旨在确定新型的遗传和串行自身抗体签名对SLE临床过程的贡献。我们将利用一个独特的机会，探索横截面和纵向结果，其DNA序列的变化以及从种族多样性，良好的SLE患者中获得的自身抗体，同时利用了人类基因组测序和高分辨率抗原微阵列技术的最新技术进步。在该提案范围内，我们打算利用现有的合作，资源和全面，高质量，临床数据和基因分型在一个良好的SLE Inception Cohort中收集的，以填补开发努力以检测，预防，管理，管理和治疗SLE所需的知识的关键空白。这种方法提供了最好的机会，可以全面地将新型的遗传和自身抗体关系与SLE临床课程作为一种预后指数，以瞄准可能受益于个性化的临床管理或治疗性干预措施的高风险脆弱人群。