Metabolomics of CKD and CKD Progression

 描述(申请人提供)：对于CKD生物标记物的研究来说，对血浆代谢组的系统调查是一种很有前途的方法，因为CKD位于各种代谢紊乱的交叉点，因为肾功能对循环代谢物有广泛的影响，并且循环代谢物本身可能参与疾病的发病机制。我们建议对慢性肾功能不全队列(CRIC)研究中1800名受试者的血浆进行基于液相色谱和质谱学的代谢物分析，目的是发现CKD进展的新的基于血液的生物标志物；了解这些代谢物与估计的肾小球滤过率(EGFR)、蛋白尿水平和其他CKD表型的横断面关联；并将代谢物数据与已经进行的基因分型相结合。目的1将使用多变量COX回归来检验基线代谢物水平与终末期肾病或EGFR减半的综合事件发生时间结果之间的关系。我们将验证色氨酸和精氨酸水平降低以及cAMP水平升高是CKD进展的标志这一假设，并对所有测量的代谢物水平进行不可知性检查。目的2将评估血浆代谢物如何随CKD严重程度(EGFR和蛋白尿水平)的变化以及与CKD现有代谢紊乱标志物(白蛋白、临床血脂、胰岛素、晚期糖基化终末产物、甲状旁腺素、成纤维细胞生长因子23、磷酸盐、hsCRP和IL-6)的关系。AIM 3将进行全基因组关联研究，以确定AIMS 1和2中强调的CKD和CKD进展的代谢物生物标记物的因果决定因素，并评估这些标记是否受先前与CKD相关的遗传位点的调节。这些研究将允许评估新的标记物是否属于因果途径，并且与先前的代谢组学不同，GWAS将检查CKD及其代谢前驱因素丰富的种族多样性人群。除了这些科学目标之外，在目标4中，我们寻求将审评委建立为验证 生物标记物的发现是CKD生物标记物联盟更广泛努力的一部分。由于广泛的研究数据和对慢性肾脏病及其并发症的明确关注，审评委的研究具有独特的地位，可以催化提案的每个组成部分，审评委指导委员会坚定地致力于丰富更广泛的联合体活动。重要的是，对一系列肾脏疾病的初步研究证明了所有所述目标的可行性。此外，该提案结合了技术改进，极大地扩大了我们代谢组学平台的广度，现在包括约350种已知代谢物和&gt；5000个未知代谢物峰，从而扩大了我们之前研究的代谢物的范围。最后，所有数据将通过DBGaP公开，就像我们团队之前的代谢组学和GWAS数据一样，为研究界提供强大的资源。

 DESCRIPTION (provided by applicant): A systematic survey of the plasma metabolome is a promising approach for CKD biomarker research because CKD lies at the intersection of various metabolic disorders, because of the broad impact renal function has on circulating metabolites, and because circulating metabolites may themselves participate in disease pathogenesis. We propose to perform liquid chromatography, mass spectrometry based metabolite profiling on plasma obtained at study entry from 1800 individuals in the Chronic Renal Insufficiency Cohort (CRIC) Study with the goal to discover novel blood-based biomarkers of CKD progression; to understand the cross- sectional association of these metabolites with estimated glomerular filtration rate (eGFR), level of proteinuria, and other CKD phenotypes; and to integrate the metabolite data with genotyping that has already been performed. Aim 1 will use multivariable Cox regression to examine the relation between baseline metabolite levels and a composite time-to-event outcome of end-stage renal disease or halving of eGFR. We will test the hypothesis that decreased tryptophan and arginine levels and increased cAMP levels are markers of CKD progression, as well as conduct an agnostic examination of all measured metabolite levels. Aim 2 will assess how plasma metabolites vary across levels of CKD severity (eGFR and level of proteinuria) and in relation to existing markers of disordered metabolism in CKD (albumin, clinical lipids, insulin, advanced glycation end- products, PTH, FGF-23, phosphate, hsCRP, and IL-6). Aim 3 will perform a genome wide association study (GWAS) to identify causal determinants of metabolite biomarkers of CKD and CKD progression highlighted in Aims 1 and 2, and to assess whether these markers are modulated by genetic loci that have previously been associated with CKD. These studies will permit assessment of whether novel markers belong to causal pathways, and unlike prior metabolomics GWAS would examine a racially diverse population enriched for CKD and its metabolic antecedents. In addition to these scientific objectives, in Aim 4 we seek to establish CRIC as a platform for the validation of novel biomarkers discovered as part of the wider CKD Biomarker Consortium efforts. With extensive study data and an explicit focus on CKD and its complications, the CRIC Study is uniquely positioned to catalyze each component of the proposal, and the CRIC Steering Committee is strongly committed to enriching the broader consortium activities. Importantly, preliminary studies across a spectrum of renal disease demonstrate feasibility for all of the stated Aims. Further, the proposal incorporates technological improvements that have dramatically increased the breadth of our metabolomics platform to now include ~350 known metabolites and >5000 unknown metabolite peaks, thus expanding the scope of metabolites surveyed beyond our prior studies. Finally, all data will be made public via dbGAP as with prior metabolomics and GWAS data generated by our group, providing a powerful resource for the research community.