Association of genetic and autoantibody signatures with SLE clinical course

描述(申请人提供)：系统性红斑狼疮(SLE)是一种典型的自身免疫性疾病，以抗核自身抗体、补体激活和多系统器官损害为特征。系统性红斑狼疮患病率和临床病程的趋势因血统而异。这种差距的基础仍然鲜为人知。尽管SLE的病因尚不清楚，但遗传和环境因素的组合起到了因果作用。这项拟议的研究的目的是描述DNA序列变异和新的高分辨率自身抗体谱与狼疮性肾炎(LN)和SLE患者严重器官损害的进展速度和严重程度之间的独立和联合影响。我们将测试压倒一切的假设，即在具有特定自身抗体谱的人中，多个基因位点的变异对极端性状SLE内表型的遗传影响更强，这可能解释了在非洲和美洲印第安人血统的患者中观察到的差异。为了验证这一总体假设，我们打算确定：(1)使用新型高分辨率抗原微阵列，自身抗体特异性对极端性状SLE内表型的存在和时间的贡献，以及祖先的差异，(2)使用Illumina高通量技术，DNA序列变异对极端性状SLE内表型的存在和时间的贡献，以及(3)DNA序列中的变异在多大程度上改变自身抗体特异性对极端性状SLE内表型的存在和时间的影响。建议的研究是一个创新的、及时的和全面的策略，以确定新的基因和系列自身抗体签名对SLE临床病程的贡献。我们将利用一个独特的机会，利用人类基因组测序和高分辨率抗原微阵列技术的最新进展，探索从不同种族、特征良好的SLE患者群体中获得的DNA序列和自身抗体的变化对横断面和纵向结果的影响。在这项提案的范围内，我们打算利用现有的合作、资源以及在具有良好特征的系统性红斑狼疮初始队列中收集的全面、高质量的临床数据和基因分型，以填补开展发现、预防、管理和治疗系统性红斑狼疮所需知识的关键空白。这种方法提供了最好的机会来综合表征新的遗传和自身抗体与SLE临床病程的关系，作为针对可能受益于个体化临床治疗或治疗干预的高危易感人群的预后指标。

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.