Association of genetic and autoantibody signatures with SLE clinical course

描述（由申请人提供）：系统性红斑狼疮（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患病率和临床病程的趋势因血统而异。人们对这种差异的基础仍然知之甚少。虽然SLE的病因尚不清楚，但遗传和环境因素的组合起着因果作用。这项研究的目的是描述DNA序列变异与新的高分辨率自身抗体谱的独立和联合作用，这些变异与SLE患者狼疮性肾炎（LN）和严重器官损害的进展率和严重程度有关。我们将测试的总体假设，极端性状SLE内表型的遗传效应，导致多个基因座的变化是更强的人与特定的自身抗体谱，这可能是非洲和美洲印第安人血统的患者之间观察到的差异。为了检验这一总体假设，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特征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序列的变异在多大程度上改变了自身抗体特异性对极端特征SLE内表型的存在和出现时间的影响。这项研究是一项创新的、及时的和全面的策略，以确定新的遗传和系列自身抗体特征对SLE临床过程的贡献。我们将利用一个独特的机会，探讨从种族多样性，特征良好的SLE患者人群中获得的DNA序列和自身抗体变异的横截面和纵向结果，同时利用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。在本提案的范围内，我们打算利用现有的合作，资源和全面的，高质量的临床数据和基因分型收集在一个良好的特点SLE初始队列，以填补知识的关键差距，发展努力，以检测，预防，管理和治疗SLE。这种方法提供了最好的机会，全面表征新的遗传和自身抗体与SLE临床病程的关系，作为针对高危脆弱人群的预后指标，可能受益于个性化的临床管理或治疗干预。

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.