Metabolomics of CKD and CKD Progression

 描述（由申请方提供）：血浆代谢组的系统性调查是CKD生物标志物研究的一种有前景的方法，因为CKD处于各种代谢紊乱的交叉点，因为肾功能对循环代谢物具有广泛的影响，并且因为循环代谢物本身可能参与疾病的发病机制。我们建议对从慢性肾功能不全队列（CRIC）研究中的1800名个体在研究进入时获得的血浆进行基于液相色谱、质谱的代谢物分析，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表型的横截面关联;并将代谢物数据与已经进行的基因分型相结合。目的1将使用多变量考克斯回归来检查基线代谢物水平与终末期肾病或eGFR减半的复合至事件时间结局之间的关系。我们将检验色氨酸和精氨酸水平降低和cAMP水平升高是CKD进展标志物的假设，并对所有测量的代谢物水平进行不可知检验。目的2将评估血浆代谢物在CKD严重程度水平（eGFR和蛋白尿水平）之间的变化以及与CKD代谢紊乱的现有标志物（白蛋白、临床脂质、胰岛素、晚期糖基化终产物、PTH、FGF-23、磷酸盐、hsCRP和IL-6）的关系。目的3将进行全基因组关联研究（GWAS），以确定目的1和2中强调的CKD和CKD进展的代谢物生物标志物的因果决定因素，并评估这些标志物是否受到先前与CKD相关的遗传基因座的调节。这些研究将允许评估新的标志物是否属于因果途径，与先前的代谢组学不同，GWAS将检查一个种族多样化的人群，该人群富含CKD及其代谢前体。除了这些科学目标外，在目标4中，我们寻求将审评委建立为一个平台， 作为更广泛的CKD生物标志物联盟努力的一部分发现的生物标志物。审评委的研究报告拥有广泛的研究数据，并明确侧重于慢性肾脏病及其并发症，因此，审评委的研究报告具有独特的地位，可以促进提案的每一个组成部分，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既定目标的可行性。此外，该提案纳入了技术改进，大大增加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>5000种未知代谢物峰，从而扩大了我们先前研究之外的代谢物范围。最后，所有数据都将通过dbGAP公开，就像我们小组之前生成的代谢组学和GWAS数据一样，为研究社区提供强大的资源。

 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.