Genetic Determinants of Renal Transplant Survival from African American Donors

描述（由申请人提供）：肾移植是终末期肾病患者的首选治疗方式。与透析相比，移植可以改善生活质量，延长患者生存期，并大幅降低成本。进展 药物治疗显著改善了死亡供体肾移植（DDKT）的短期存活率;然而，长期结果仍然很差，非洲裔美国人（AA）的十年移植存活率仅为33.8%，显著短于欧洲裔美国人（EA）的45%存活率。迫切需要改善移植物长期存活的新工具。肾脏供体中载脂蛋白L1（APOL 1）、编码P-糖蛋白的多药耐药1（ABCB 1）和小窝蛋白-1（CAV 1）基因的遗传风险变异显著缩短了同种异体移植物的生存期，为供体肾脏基因变异影响移植结果提供了强有力的证据。该建议将系统地寻找影响AA供体DDKT后移植物存活的遗传和环境因素。我们建议在58个重复的肾病易感基因座中检测变异与AA供体肾移植物长期存活的相关性。 将评估基因变异彼此之间以及与环境压力因素之间的相互作用。然后将评估含有与同种异体移植失败相关的风险变体的人原代肾细胞中支持遗传关联结果的基因表达谱的改变。分析将分两个阶段进行：发现阶段涉及600个无关AA供体肾DNA样本的遗传数据（产生800-900个移植物），并在基因表达分析和后续基因 * 基因和基因 * 环境相互作用研究中进行验证。将在所有800名AA肾脏供体中进行沿着额外200份AA DDKT DNA样本的复制阶段和合并分析。将在肾移植受者DNA样本中评估顶级供体基因关联，以确定效应是否特异于供体肾脏。这58种肾病风险变异提高了我们对肾脏疾病发病机制的理解;然而，大多数影响相对较弱，预测能力较低，限制了临床应用。我们提出了一种系统的方法，分析在肾移植的全基因组关联研究中发现的肾病基因，其中器官因长期缺乏灌注和暴露于肾毒性药物而受到压力。这些因素可能提供了一个合适的对比，以检测肾移植物存活的遗传因素。这项工作可能会改善来自非洲血统捐赠者的DDKT后的结果，并允许在重要的临床领域翻译遗传结果。

DESCRIPTION (provided by applicant): Kidney transplantation is the preferred treatment modality for patients with end-stage kidney disease. Compared to dialysis, transplantation leads to improved quality of life, longer patient survival, and considerable cost reductions. Progress in medical therapy has dramatically improved short-term survival of deceased donor kidney transplants (DDKT); however, long-term results remain poor with ten year graft survival rates of only 33.8% in African Americans (AAs), significantly shorter than the 45% survival in European Americans (EAs). New tools to improve long-term graft survival are urgently needed. Genetic risk variants in the Apo lipoprotein L1 (APOL1), multi-drug resistance 1 encoding P-glycoprotein (ABCB1), and caveolin-1 (CAV1) genes in kidney donors significantly shorten allograft survival, providing strong evidence that donor kidney gene variants impact transplant outcomes. This proposal would systematically search for genetic and environmental factors that impact graft survival after DDKT from AA donors. We propose to test variants in 58 replicated nephropathy susceptibility loci for association with long-term kidney transplant graft survival from AA donors. Interactive effects of gene variants with each other and with environmental stressors will be assessed. Human primary kidney cells containing the risk variants associated with allograft failure will then be assessed for alterations in gene expression profiles supporting the genetic association results. Analyses will be conducted in two phases: a discovery phase involving genetic data in 600 unrelated AA donor-kidney DNA samples (yielding 800-900 transplants) with validation in gene expression analyses and follow-up gene*gene and gene*environment interaction studies. A replication phase with an additional 200 AA DDKT DNA samples will be performed along with a combined analysis in all 800 AA kidney donors. Top donor gene associations will be assessed in kidney transplant recipient DNA samples to determine whether effects are specific to donor kidneys. These 58 nephropathy risk variants have improved our understanding of the pathogenesis of kidney disease; however, most have relatively weak effects and low predictive ability limiting clinical utility. We propose a systematic approach, analyzing nephropathy genes identified in genome-wide association studies in kidney transplantation where organs are stressed by prolonged lack of perfusion and exposure to nephrotoxic medications. These factors likely provide a suitable contrast to detect genetic contributors to renal graft survival. This work will likely improve outcomes after DDKT from donors of African ancestry and allow translation of genetic results in an important clinical realm.