Abstract
Improvements in immunosuppression have modified short‐term survival of deceased‐donor allografts, but not their rate of long‐term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short‐ and long‐term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large‐scale genome‐wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant‐pairs with replication in 5866 complete pairs. We studied deceased‐donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long‐ or short‐term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.
Highlights
Kidney transplantation is a highly successful treatment for end- stage renal failure, with significant benefits for recipients both in survival and quality of life
A small number of Genome-wide association studies (GWAS) have been reported in the field of renal transplantation, describing single nucleotide polymorphisms (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]
3936 samples comprising 2094 complete donor-recipient pairs were tested in the GWAS discovery phase, and an additional 5866 complete donor-recipient pairs in the replication phase, making this the largest GWAS conducted to date in renal transplantation outcomes
Summary
Kidney transplantation is a highly successful treatment for end- stage renal failure, with significant benefits for recipients both in survival and quality of life. Some of the reasons for this may include small sample sizes, variations in genotyping methodology and strategy, and, perhaps most importantly, a lack of consistency in clinical phenotyping.[20] Genome-wide association studies (GWAS) have contributed greatly to an increased understanding of complex common conditions such as inflammatory bowel disease, hypertension, type 2 diabetes, and schizophrenia.[21] 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] these studies were underpowered for discovery of genetic variants with small effect sizes. 3936 samples comprising 2094 complete donor-recipient pairs were tested in the GWAS discovery phase, and an additional 5866 complete donor-recipient pairs in the replication phase, making this the largest GWAS conducted to date in renal transplantation outcomes
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