A National Consortium to Explore the Genotypic Basis for ESRD in Lupus

描述(申请人提供)：终末期肾病(ESRD)是系统性红斑狼疮(SLE)最严重和最昂贵的并发症之一，发生在与SLE相关的肾脏受累的亚组患者中。ESRD的易感因素可能包括遗传和环境因素，而且有明确的证据表明，ESRD对非裔美国人后裔的狼疮患者的影响不成比例。与SLE相关的ESRD的数据表明，至少有两个遗传因素--FCGR3A和Myh9基因的某些等位基因变异--导致了ESRD的风险。然而，仅有两个基因并不能定义终末期肾病的遗传风险范围。因此，基于我们关于基因贡献的先例数据，现在是时候进行全基因组关联研究(Gwas)，以确定患有狼疮性肾炎(LN/ESRD)的欧洲裔美国人(EA)和非裔美国人(AA)ESRD的遗传危险因素。到目前为止，有两个主要障碍阻碍了这样的研究。Illumina Human Omni-1四芯片克服了基因分型平台和覆盖范围的技术限制。为了克服研究人群有限的第二个障碍，我们组建了一支史无前例的风湿科医生、肾病学家和统计遗传学家团队，他们启动了IRB方案，临床研究基础设施到位，患者收集和临床数据超过75%。因此，(1)我们的第一个目的是通过对不同种族的狼疮患者进行800 EA LN/ESRD和800 AA LN/ESRD的研究，以确定与ESRD相关的遗传易感因素，并与无肾炎的狼疮患者和正常对照组进行比较。(2)我们认为[基因x基因]和[基因x环境]的相互作用在生物学上是重要的，并且可能更容易使用机器学习和更现代的基于似然的方法来检测。因此，我们的第二个目标是将新的方法应用于基因发现和生物路径表征，包括贝叶斯网络、替代决策树、HyperLasso和惩罚Logistic回归。(3)最后，我们的第三个目标是建立一个基本的资源，与NIH的标本和数据共享指南保持一致，并得到该机构的支持。这一资源将使后续研究能够进行精细测绘、深度测序、SNP鉴定、途径分析和方法开发。我们的财团利用NIAMS、NIDDK、NIEHS、NCRR、CDCP和私人基金会目前的资源和投资，创造了一个独特的机会来应对重大的医疗挑战。我们利用已建立的网络和临床研究基础设施，拥有相当大的领先优势，并准备识别遗传风险因素，从而制定减少ESRD的战略，这将使我们能够大幅节省成本，降低发病率和死亡率，因为它减少了健康结果中的种族差异。

DESCRIPTION (provided by applicant): End stage renal disease (ESRD), one of the most serious and costly complications of systemic lupus erythematosus (SLE), occurs in a sub-set of patients with SLE-related renal involvement. Factors predisposing to ESRD presumably include both genetics and environmental factors, and there is unequivocal evidence that ESRD disproportionately affects lupus persons of African American descent. Data in SLE-related ESRD suggest that at least two genetic factors, -- certain allelic variants of the genes FCGR3A and MYH9, -- contribute to ESRD risk. However, two genes alone do not define the scope of genetic risk for ESRD. Therefore, building on our precedent data for genetic contributions, it is timely to undertake a genome-wide association study (GWAS) to identify the genetic risk factors for ESRD in European American (EA) and African Americans (AA) with lupus nephritis (LN/ESRD). Until now, two major barriers have precluded such a study. Technical limitations in genotyping platform and coverage have been overcome with the Illumina Human Omni- 1 Quad BeadChip. To surmount the second barrier of limited study populations, we have assembled an unprecedented team of rheumatologists, nephrologists and statistical geneticists with IRB protocols active, the clinical studies infrastructure in place and the patient collections and clinical data more than 75% in hand. Thus (1) Our first aim is to characterize the genetic susceptibility factors associated with ESRD by performing a GWAS with 800 EA LN/ESRD and 800 AA LN/ESRD compared to lupus subjects of each ethnicity but without nephritis and normal control subjects. (2) We propose that [gene x gene] and [gene x environment] interactions are biologically important and may be more easily detectable using the machine learning and more modern likelihood-based approaches. Therefore, our second aim is to apply novel approaches to gene discovery and biological pathway characterization including Bayesian networks, alternative decision trees, HyperLasso, and penalized logistic regression. (3) Finally, our third aim is to build an essential resource, consistent with NIH specimen and data sharing guidelines and supported by the institution. This resource will enable follow-up studies in fine-mapping, deep-sequencing, SNP identification, pathway analysis and methods development. Our consortium leverages current resources and investments by NIAMS, NIDDK, NIEHS, NCRR, CDCP and private foundations to create a unique opportunity to address a major health care challenge. We have a substantial head start, drawing on established networks and clinical research infrastructure, and are poised to identify genetic risk factors, leading to strategies for ESRD reduction, which would enable substantial cost savings and reduction in morbidity and mortality as it reduces ethnic disparities in health outcomes.