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Risk of Chronic Kidney Disease Associated with GSTM1 Deletions

与 GSTM1 缺失相关的慢性肾脏病风险

基本信息

批准号：
9353398
负责人：
ADRIENNE TIN
金额：
$ 20.44万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9353398
关键词：
Adult Affect African American Algorithms American Area Atherosclerosis Risk in Communities Attention Biological Candidate Disease Gene Chronic Kidney Failure Cohort Studies Copy Number Polymorphism DNA copy number Data Disease Outcome Disease Progression European Excretory function Genes Genetic Predisposition to Disease Genetic study Genotype Glutathione Glutathione Metabolism Pathway Hypertension Kidney Kidney Diseases Lead Measures Mediating Metabolic Pathway Methods Modification Outcome Oxidative Stress Participant Pathway interactions Patients Polymerase Chain Reaction Prevention Pyrrolidonecarboxylic Acid Reporting Resources Risk Risk Factors Running Single Nucleotide Polymorphism Smoker Smoking Validation Variant Work base biological adaptation to stress cohort cost effective data resource disorder risk effective therapy exome exome sequencing genetic information glutathione S-transferase M1 high risk insight metabolomics non-smoker novel personalized medicine protein function therapeutic target validation studies

项目摘要

Chronic kidney disease (CKD) affects ~10% of the U.S. adults and has few effective treatments. Studies of genetic susceptibility can provide insight into the underlying causal pathways and may lead to novel treatment targets. One promising candidate gene for CKD is the glutathione S- transferase mu 1 (GSTM1), which catalyzes the conjugation of glutathione with a range of electrophiles to facilitate the degradation or excretion of the electrophiles. Loss of the GSTM1 gene has been associated with two-fold higher risk for CKD progression in the African American Study of Kidney Disease and Hypertension (AASK). The GSTM1 homozygous deletion (0 copy) is a common variant (27% in African Americans and 53% in European Americans) and cannot be tagged reliably using single nucleotide polymorphisms (SNPs). Large scale association studies of the GSTM1 copy number variation (CNV) with kidney outcome have not been conducted. Recent availability of large scale exome sequencing data provides an unprecedented opportunity for determining exonic CNVs, which are likely to change protein function. The Atherosclerosis Risk in Communities (ARIC) study have existing exome sequencing data in ~7800 European Americans and ~3000 African Americans, carefully measured CKD risk factors and validated CKD outcomes. Using the rich data resources in the ARIC study, we aim to 1) determine GSTM1 CNV using exome sequencing reads and validate the CNV calls using an enhanced quantitative polymerase chain reaction (qPCR) method in a subsample (N=224); 2) characterize the association between the GSTM1 CNV with incident CKD and its progression; 3) Identify metabolites in the glutathione pathway that mediate CKD risk associated with GSTM1 CNV. Exome sequencing reads provides a novel and cost effective resources for determining exonic CNVs. Few studies have investigated the association between exonic CNVs and CKD with validation on the CNV calls. Leveraging the long-running ARIC study with exome sequencing and metabolomic data, we can conduct large-scale association studies of the GSTM1 CNV. This proposal will result in substantial enhancements to the CNV calling algorithms, which can be applied to other known exonic CNVs in the ARIC study and other large cohort studies in which we may validate associations. If GSTM1 deletion is found to be underlying CKD risk, GSTM1 and its metabolic pathways can be a potential target for the prevention and treatment of CKD.

慢性肾脏病（CKD）影响约10%的美国成年人，并且几乎没有有效的治疗方法。研究遗传易感性可以提供深入了解潜在的因果途径，并可能导致新的治疗方法目标的一个有希望的CKD候选基因是谷胱甘肽S-转移酶μ 1（GSTM 1），催化谷胱甘肽与一系列亲电试剂的结合，以促进降解或排泄亲电体的GSTM 1基因缺失与CKD风险增加两倍相关非裔美国人肾脏疾病和高血压研究（AASK）。GSTM 1 纯合缺失（0拷贝）是一种常见变异（在非裔美国人中为27%，在欧洲人中为53 美国人），并且不能使用单核苷酸多态性（SNP）可靠地标记。大规模 GSTM 1拷贝数变异（CNV）与肾脏预后的相关性研究尚未得到证实。进行。最近大规模外显子组测序数据的可用性提供了前所未有的机会用于确定外显子CNV，这可能会改变蛋白质功能。动脉粥样硬化风险社区（ARIC）研究在约7800名欧洲裔美国人和约3000名非裔美国人，仔细测量CKD风险因素和验证CKD结果。利用丰富的数据在ARIC研究中，我们的目标是1）使用外显子组测序读数确定GSTM 1 CNV，并验证在子样本中使用增强的定量聚合酶链反应（qPCR）方法进行CNV调用（N=224）; 2）表征GSTM 1 CNV与CKD事件及其进展之间的关联; 3）确定谷胱甘肽途径中介导与GSTM 1 CNV相关的CKD风险的代谢物。外显子组测序读数为确定外显子CNV提供了新的和成本有效的资源。很少有研究已经研究了外显子CNV和CKD之间的关联，并对CNV调用进行了验证。利用通过外显子组测序和代谢组学数据的长期ARIC研究，我们可以进行大规模的 GSTM 1 CNV的相关研究。这一建议将大大增强CNV 调用算法，可应用于ARIC研究和其他大型队列中的其他已知外显子CNV 我们可以验证关联的研究。如果发现GSTM 1缺失是潜在的CKD风险，则GSTM 1 其代谢途径可能成为CKD防治的潜在靶点。