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

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.

Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort

“…18 Genotyping details for the Dublin and Tennessee cohorts were described previously. 18 Genotyping details for the Dublin and Tennessee cohorts were described previously.…”

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

“…6 However, this study was limited by its sample size (n = 326) and an independent effort failed to replicate the findings. 7 Although much better powered than earlier efforts, no significant associations were found beyond the previously known effect of the HLA. 7 Although much better powered than earlier efforts, no significant associations were found beyond the previously known effect of the HLA.…”

“…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.…”

The genetic determinants of renal allograft rejection

“…The 2 recipient genetic loci highlighted in their paper,3 rs10765602 (gene annotation CCDC67 ) and rs7976329 (gene annotation PTPRO ), were well imputed in our study (INFO>0.95) and neither reached genome‐wide significance in our reported analyses 2. To provide additional confidence, we have reanalyzed our data following reimputation to the 1000 Genomes phase 3 reference panel via the Sanger Imputation Service (www.…”

“…We thank Massart et al for their comments1 on our recently published large‐scale genome‐wide association study of renal transplant outcomes,2 and we welcome the opportunity to examine their findings in more detail.…”