Metabolomics and Genomics in African Americans with CKD

患有 CKD 的非裔美国人的代谢组学和基因组学

• 批准号: 9922283
• 负责人: Morgan Erika Grams
• 金额: $ 57.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-13 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922283
• 关键词: Affect; African; African American; Albuminuria; Apolipoproteins; Bilirubin; Biological; Caring; Caucasians; Cell physiology; Cessation of life; Chronic Kidney Failure; Clinical; Collection; Cresol; Critical Pathways; Data; Disease Outcome; Disease Progression; Disease susceptibility; End stage renal failure; Erythrocytes; Ethnic group; Etiology; Evaluation; General Population; Genes; Genetic; Genetic Determinism; Genetic Risk; Genetic Variation; Genomics; Genotype; Glomerular Filtration Rate; Hypertension; Incidence; Indican; Intervention; Kidney; Kidney Diseases; Knowledge; Lead; Link; Longitudinal Studies; Mediating; Mediator of activation protein; Medical; Methods; Mutation; New York City; Outcome; Outpatients; Participant; Pathogenicity; Pathologic Processes; Pathway interactions; Patients; Pattern; Phenotype; Pilot Projects; Population; Process; Randomized; Renal function; Research; Resources; Risk; Risk Factors; Role; Sampling; Sickle Cell; Sickle Cell Trait; Sulfate; Techniques; Toxin; Variant; Visit; Work; alpha-Thalassemia; base; bile acid metabolism; cohort; design; disorder prevention; disorder risk; ethnic difference; follow-up; gene function; genetic risk factor; genetic variant; genome wide association study; genomic data; high risk; improved; metabolomics; modifiable risk; mortality; novel; public health relevance; racial disparity; renal damage; risk variant; targeted treatment

? DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) disproportionately affects African Americans. Two recent discoveries suggest that common, African-specific genetic risk factors are particularly relevant in CKD susceptibility. Variants in the gene encoding apolipoprotein L1 (APOL1) and the presence of a single copy of the sickle cell mutation (sickle cell trait, or SCT) both increase the risk of CKD progression. How these variants confer kidney risk, whether there is gene-gene interplay, and the identity of any causal intermediates is unknown. The proposed studies will use two complementary cohorts of African Americans with CKD, the African American Study of Kidney Disease and Hypertension (AASK) and a subset of BioMe, to investigate these questions. The AASK study is arguably the most comprehensively phenotyped of African Americans with CKD in the world, assessing participants' kidney function every 6 months for up to 12 years (and up to 17 years for end-stage renal disease and death). BioMe is an ongoing, contemporary cohort of patients receiving medical care in New York City, with substantial resources devoted to biospecimen collection and genotyping. The analysis will build upon our prior work in genetic risk factors for CKD by investigating novel variants and their relationship to kidney function decline as well as gene-gene interplay in risk for adverse CKD outcomes. In addition, we will study the relationship of metabolomic patterns - a snapshot of the end-product of cellular processes - with CKD outcomes. This analysis can lead to identification of novel and potentially modifiable risk factors for CKD outcomes. When combined with genomic data, the metabolomic consequences of genetic risk variants such as the APOL1 high-risk genotype or SCT can be studied. In addition, analytic techniques can help distinguish whether metabolomic risk factors cause adverse CKD outcomes or are simply a byproduct of an associated process. Understanding the relationship between genomics, metabolomics, and outcomes will advance knowledge regarding pathogenic pathways and potentially modifiable targets in CKD progression, particularly in African Americans, an ethnic group disproportionately affected with advanced CKD.

? 描述（由申请人提供）：慢性肾脏疾病（CKD）不成比例地影响非洲裔美国人。最近的两项发现表明，常见的非洲特异性遗传风险因素与CKD易感性特别相关。基因编码的变异体 载脂蛋白L1（APOL 1）和镰状细胞突变（镰状细胞性状，或SCT）的单拷贝的存在都增加了CKD进展的风险。这些变异如何赋予肾脏风险，是否存在基因-基因相互作用，以及任何因果中间体的身份尚不清楚。拟议的研究将使用两个互补的非裔美国人CKD队列，非裔美国人肾脏疾病和高血压研究（AASK）和BioMe的一个子集来调查这些问题。AASK研究可以说是世界上最全面的非裔美国人CKD表型，每6个月评估参与者的肾功能长达12年（终末期肾病和死亡长达17年）。BioMe是一个正在进行的，在纽约市接受医疗护理的当代患者队列，有大量的资源专门用于生物标本收集和基因分型。该分析将建立在我们先前在CKD遗传风险因素方面的工作基础上，通过调查新的变异及其 与肾功能下降的关系以及基因-基因相互作用对CKD不良结局的风险。此外，我们还将研究代谢组学模式（细胞过程终产物的快照）与CKD结局的关系。这种分析可以识别CKD结局的新的和潜在的可改变的风险因素。当与基因组数据相结合时，可以研究遗传风险变体（如APOL 1高风险基因型或SCT）的代谢组学后果。此外，分析技术可以帮助区分代谢组学风险因素是否会导致不利的CKD结果，或者仅仅是相关过程的副产品。了解基因组学、代谢组学和结局之间的关系将促进对CKD进展中致病途径和潜在可改变靶点的了解，特别是在非裔美国人中，这是一个不成比例地受晚期CKD影响的种族群体。