Genetic Epidemiology of Deterioration of Kidney Allograft Function

尽管移植肾的一年存活率有所改善，但慢性移植肾功能障碍(CGD)和随后的 晚期移植物丢失仍然是主要的临床问题。这一建议的目的是确定等位基因是否 参与免疫反应(通过细胞因子和趋化因子)、纤维化、生长调节的基因变体 因子、血管黏附分子和高血压与(1)持续性CGD相关 在移植后3个月建立的基线基础上，血清肌酐增加了25%(2) 在不同种族的移植中，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。我们的 SubAim#1将比较与CGD和EGFR相关的等位基因变异在 非洲裔美国人和非非洲裔美国人获奖者。我们的次级目标#2将研究接受者之间的互动 巨细胞病毒暴露和受体免疫反应基因与CGD和EGFR的等位变异。 了解CGD和EGFR潜在决定因素的遗传变异可能会提出更好的建议 延长同种异体肾移植功能的治疗方法。研究的目标将是 通过正在进行的NIH登记的多中心、预期的肾移植受者队列完成 研究肾功能恶化期间移植肾活检的资助研究。 次要终点将是血清肌酐持续增加25%和数量和 肾活检的半定量病理表现。前1000名受试者的测试集将是 用Affymetrix定制的SNP芯片进行基因分型，大约有3500个SNP代表1025个基因 来自47种不同的生物途径。那些与研究结果相关的SNPs 测试队列将在随后的4000名移植受者的验证队列中进一步进行基因分型 目标1和AIM2的2000名活体捐赠者。验证队列还将生成单倍型 选定的候选基因。AIM 2的一个子项目也将探索活体捐赠者的多基因效应的影响 以及CGD上的受体基因型和EGFR持续下降25%。比例风险模型将 探讨候选基因多态与CGD发病时间或25%之间的关系 EGFR下降。还将进行单倍型分析。多基因效应将用一种 各种分析技术。这些方法包括统计和概率方法，如贝叶斯方法 分类器和聚类以及有监督的机器学习方法，如决策树归纳 以及基于进化计算的学习分类器系统。通过识别基因多态 影响CGD和EGFR，这项研究将有助于识别有风险的患者，并将有助于制定 以关键路径为目标的疗法。

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.