Genetic Epidemiology of Deterioration of Kidney Allograf

同种异体肾恶化的遗传流行病学

• 批准号: 7148471
• 负责人: AJAY K ISRANI
• 金额: $ 33.89万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148471
• 关键词: African American; alleles; biopsy; caucasian American; computational biology; cooperative study; creatinine; cytokine; cytomegalovirus; fibrosis; gene environment interaction; genetic polymorphism; genetic susceptibility; genotype; glomerular filtration rate; growth factor; homologous transplantation; human subject; hypertension; immune response; immunogenetics; kidney function; kidney transplantation; patient oriented research; postoperative state; racial /ethnic difference; tissue donors; transplant rejection; vascular cell adhesion molecule

Despite improvements in 1-year kidney allograft survival, chronic graft dysfunction (CGD) and subsequent late graft loss persists as major clinical problem. The objective of this proposal is to determine whether allelic variants of genes involved in regulation of immune response (via cytokines and chemokines), fibrosis, growth factors, vascular adhesion molecules and hypertension are associated with (1) CGD defined as persistent 25% increase in serum creatinine from a baseline established at 3 months post-transplantation and (2) persistent 25% decline in estimated glomerular filtration rate (eGFR), in a racially diverse transplant population. AIM 1 will study recipient candidate genes and AIM 2 will study the living donor genes. Our subaim #1 will compare the frequency of allelic variants that are associated with CGD and eGFR among African Americans and non-African American recipients. Our subaim #2 will study the interaction of recipient cytomegalovirus exposure and allelic variants of recipient immune response genes with CGDand eGFR. Understanding the genetic variants of potential determinants of CGD and eGFR may suggest better therapeutic approaches that extend the function of the kidney allografts. The research aims will be accomplished via a multicenter, prospective cohort of kidney transplant recipients enrolled in an ongoing NIH funded study studying kidney allograft biopsies during deterioration of kidney function. Secondary endpoints will be a composite of persistent 25% increase in serum creatinine and quantitative and semi-quantitative pathological findings on kidney biopsy. A test set of the first 1000 subjects will be genotyped using an Affymetrix custom SNP chip with approximately 3500 SNPs representing 1025 genes from 47 different biological pathways. Those SNPs with an association with the outcomes of interest in the Test cohort will be further genotyped in the subsequent Validation Cohort of 4000 transplant recipients for Aim 1 and for 2000 living donors for Aim2. The Validation cohort will also generate haplotypes of the selected candidate genes. A Subaim of Aim 2 will also explore the impact of multigene effects of living donor and recipient genotypes on CGD and a persistent 25% decline in eGFR. A proportional hazards model will be implemented to explore the relationship of the candidate gene polymorphisms with time to CGD or a 25% decline in eGFR. Haplotype analysis will also be conducted. Multi-gene effects will be explored using a variety of analytical techniques. These include statistical and probabilistic methods such as Bayesian classifiers and clustering as well as supervised machine learning methods such as decision tree induction and evolutionary computation-based learning classifier systems. By identifying genetic polymorphisms that impact CGD and eGFR, this study will help identify patients at risk and will help in the development of therapies targeting critical pathways.

尽管1年移植肾存活率有所改善，但慢性移植物功能障碍（CGD）和随后的 晚期移植物丢失仍然是主要的临床问题。这项建议的目的是确定是否等位基因 参与调节免疫应答（通过细胞因子和趋化因子）、纤维化、生长的基因变体 因子、血管粘附分子和高血压与（1）定义为持续性的CGD相关 血清肌酐较移植后3个月建立的基线增加25%，以及（2） 在一项种族多样性移植中，估计肾小球滤过率（eGFR）持续下降25% 人口AIM 1将研究受体候选基因，AIM 2将研究活体供体基因。我们 子目标#1将比较与CGD和eGFR相关的等位基因变异的频率， 非裔美国人和非裔美国人。我们的子目标#2将研究接受者的相互作用 巨细胞病毒暴露和受体免疫应答基因的等位基因变体与CGD和eGFR。 了解CGD和eGFR潜在决定因素的遗传变异可能更好地提示 扩大肾移植功能的治疗方法。研究目的将是 通过一项正在进行的NIH研究中招募的多中心、前瞻性肾移植受者队列完成 一项研究在肾功能恶化时对移植肾进行活检的资助研究。 次要终点将是血清肌酐持续升高25%和定量和 肾活检的半定量病理结果。前1000名受试者的测试集将 使用具有代表1025个基因的约3500个SNP的Affyphon定制SNP芯片进行基因分型 来自47种不同的生物学途径那些与研究中感兴趣的结果相关的SNP， 在随后的4000名移植受者的验证队列中，将对测试队列进行进一步的基因分型， 目标1和目标2的2000名活体捐献者。验证组群还将生成以下基因的单倍型： 选择候选基因。Aim 2的一个子项目还将探讨活体供者多基因效应的影响。 CGD和受体基因型，eGFR持续下降25%。比例风险模型将 实施以探索候选基因多态性与CGD或25% eGFR下降。还将进行单倍型分析。多基因效应将使用 各种分析技术。这些方法包括统计和概率方法，如贝叶斯 分类器和聚类以及监督机器学习方法，如决策树归纳 和基于进化计算的学习分类器系统。通过鉴定遗传多态性， 影响CGD和eGFR，这项研究将有助于识别有风险的患者， 针对关键途径的治疗。