Genetic Epidemiology and Renal Allograft Outcomes

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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.