Genetic Epidemiology of Deterioration of Kidney Allograft Function

University Of Minnesota, Minneapolis MN

Investigators

Linked publications & trials

Abstract

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