Genetic Epidemiology and Renal Allograft Outcomes

描述（由申请人提供）：申请人是一名肾病学研究员，受过遗传学和临床流行病学的高级培训，对临床研究有长期的兴趣。该申请提出了一个全面的跨学科计划，将为申请人提供必要的技能和经验，使其发展成为肾脏遗传流行病学的独立研究者。这项指导培训计划的主要目标是获得必要的技能，成为一名独立的临床研究者和遗传流行病学家，解决肾移植中的重要问题。该项目的培训内容包括成为宾夕法尼亚大学临床流行病学主任Harold I. Feldman博士的导师，并完成正式课程和论文，获得流行病学博士学位。该研究部分的目的是确定与原发性高血压发生相关的基因等位变异是否也与同种异体肾移植存活相关。高血压对同种异体肾移植的生存有很大的负面影响。与原发性高血压相关的几个基因也在免疫反应、生长因子和纤维化的调节中发挥重要作用。了解同种异体肾移植存活的潜在决定因素的遗传变异可能允许扩展同种异体肾移植功能的治疗。研究目的将通过一项多中心、前瞻性队列研究，在特拉华河谷的成人肾移植受者中完成。以下基因的遗传多态性将通过对同种异体移植受体的DNA样本进行PCR检测：血管紧张素转换酶、血管紧张素原、血管紧张素II型1受体、醛固酮合成酶和gi蛋白β -3亚基基因。这些基因的选择是基于合理性、潜在的因果关系、发生频率和先前在相关环境中发表的验证研究。我们将采用Cox比例风险模型来探讨候选基因多态性与移植损失的关系。通过鉴定影响同种异体移植物存活的遗传多态性，这项研究将有助于鉴定有风险的患者，并有助于开发针对关键途径的治疗方法。

DESCRIPTION (provided by applicant):The applicant is a nephrology fellow with advanced training in genetics and clinical epidemiology and a longstanding interest in clinical research. This application proposes a comprehensive, interdisciplinary program that will provide the applicant with the skills and experience necessary for his development into an independent investigator in renal, genetic epidemiology. The principal objective of this mentored training proposal is to acquire the necessary skills to become an independent clinical investigator and a genetic epidemiologist addressing important issues in renal transplantation. The training component of this program includes a preceptorship with Dr. Harold I. Feldman, Chief of Clinical Epidemiology, University of Pennsylvania and completion of the formal course work and dissertation leading to a Ph.D. degree in Epidemiology. The objective of the research component is to determine whether allelic variants of genes that are associated with development of essential hypertension are also associated with renal allograft survival.Hypertension has a substantial negative impact on renal allograft survival. Several genes that are associated with essential hypertension also play an important role in the modulation of immune response, growth factors and fibrosis. Understanding genetic variants of potential determinants of renal allograft survival may allow for treatments that extend the function of kidney allografts. The research aims will be acomplished via a multicenter, prospective cohort study among adult recipients of renal allografts in the Delaware Valley. The genetic polymorphisms of the following genes will be determined by PCR of DNA samples from the allograft recipients: angiotensin-converting enzyme, angiotensinogen, angiotensin II Type 1 receptor, aldosterone synthase and the Gi-protein Beta-3 subunit gene. The selection of these genes is based on plausibility, potential causation, frequency of occurrence and previously published validation studies in related settings. A Cox proportional hazard model will be implemented to explore the relationship of the candidate gene polymorphisms with time to allograft loss. By identifying genetic polymorphisms that impact allograft survival, this study will help identify patients at risk and will help in the development of therapies targeting critical pathways.