Genome-Wide Association Study of Acute Renal Graft Rejection

Abstract

Acute renal rejection is a major risk factor for chronic allograft dysfunction and long‐term graft loss. We performed a genome‐wide association study to detect loci associated with biopsy‐proven acute T cell–mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant single nucleotide polymorphisms (SNPs) from the discovery cohort. In the discovery cohort, we found five candidate loci tagged by a number of contiguous SNPs (more than five) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor‐type tyrosine kinase essential for B cell receptor signaling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium.

A randomized clinical trial of age and genotype‐guided tacrolimus dosing after pediatric solid organ transplantation

“…CYP3A5*1/*1 genotype of donor has also been associated with higher tacrolimus dose requirements in liver transplant recipients . However, a genome‐wide association study at our center and another study by Ghisal et al did not identify association between CYP3A5 loci and biopsy‐proven rejection.…”

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population

“…9 This highlights the need for larger, robust GWAS of allograft outcome to determine the extent to which common variation affects the outcome of kidney transplantation. 8 Neither the PTPRO or CCDC67 signal replicated in the UKIRTC GWAS of acute rejection; however, the definition of acute rejection in the UKIRTC study 11 was not specific to T cell-mediated rejection which may explain the discordance. A GWAS involving pooled DNA from 4127 renal transplant recipients identified signals of association with T cell-mediated acute rejection at the PTPRO and CCDC67 loci.…”

“…1 A number of studies have examined candidate genes or variants beyond the HLA and their impact on graft function [2][3][4] ; however, few have been replicated. [6][7][8] A study from 2013 identified recipient genotype loci on chromosomes 14 and 18 which significantly associated with 5 years serum creatinine and long-term graft survival. [6][7][8] A study from 2013 identified recipient genotype loci on chromosomes 14 and 18 which significantly associated with 5 years serum creatinine and long-term graft survival.…”

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study

“…A small number of GWAS have been reported in the field of renal transplantation, describing SNPs associated with cardiovascular adverse events in recipients taking calcineurin inhibitor immunosuppression,22 2 SNPs associated with serum creatinine levels at 5 years posttransplant,23 and a number of SNPs associated with the development of new‐onset diabetes after transplantation 24. Recently, a GWAS using pooled DNA of recipient‐only origin found variation in 2 new loci associated with acute rejection in both univariate and multivariate analysis 25. However, these studies were underpowered for discovery of genetic variants with small effect sizes.…”