Multicenter Study

. 2018 Jun;18(6):1370-1379.

doi: 10.1111/ajt.14594. Epub 2018 Feb 1.

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

Maria P Hernandez-Fuentes¹, Christopher Franklin², Irene Rebollo-Mesa¹, Jennifer Mollon^{1

3}, Florence Delaney^{1

4}, Esperanza Perucha¹, Caragh Stapleton⁵, Richard Borrows⁶, Catherine Byrne⁷, Gianpiero Cavalleri⁵, Brendan Clarke⁸, Menna Clatworthy⁹, John Feehally¹⁰, Susan Fuggle¹¹, Sarah A Gagliano¹², Sian Griffin¹³, Abdul Hammad¹⁴, Robert Higgins¹⁵, Alan Jardine¹⁶, Mary Keogan¹⁷, Timothy Leach¹⁸, Iain MacPhee¹⁹, Patrick B Mark¹⁶, James Marsh²⁰, Peter Maxwell²¹, William McKane²², Adam McLean²³, Charles Newstead²⁴, Titus Augustine²⁵, Paul Phelan²⁶, Steve Powis²⁷, Peter Rowe²⁸, Neil Sheerin²⁹, Ellen Solomon³⁰, Henry Stephens²⁶, Raj Thuraisingham³¹, Richard Trembath³⁰, Peter Topham¹⁰, Robert Vaughan³², Steven H Sacks^{1

4}, Peter Conlon^{5

17}, Gerhard Opelz³³, Nicole Soranzo^{2

3}, Michael E Weale³⁰, Graham M Lord^{1

4}; United Kingdom and Ireland Renal Transplant Consortium (UKIRTC) and the Wellcome Trust Case Control Consortium (WTCCC)-3

Affiliations

¹ King's College London, MRC Centre for Transplantation, London, UK.
² Welcome Trust Sanger Institute, Human Genetics, Cambridge, UK.
³ Department of Haematology, University of Cambridge, Cambridge, UK.
⁴ NIHR Biomedical Research Centre at Guy's and St Thomas', NHS Foundation Trust and King's College London, London, UK.
⁵ Royal College of Surgeons in Ireland, Dublin, Ireland.
⁶ Renal Institute of Birmingham, Department of Nephrology and Transplantation, Birmingham, UK.
⁷ Nottingham Renal and Transplant Unit, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁸ Transplant and Cellular Immunology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
⁹ Department of Medicine, University of Cambridge, Cambridge, UK.
¹⁰ Leicester General Hospital, Leicester, UK.
¹¹ Transplant Immunology & Immunogenetics, Churchill Hospital, Oxford, UK.
¹² Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹³ Cardiff & Vale University Health Board, Cardiff University, Cardiff, UK.
¹⁴ The Royal Liverpool and Broadgreen University Hospitals, Liverpool, UK.
¹⁵ University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.
¹⁶ School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK.
¹⁷ Beaumont Hospital, Dublin, Ireland.
¹⁸ Queen Alexandra Hospital, Portsmouth, UK.
¹⁹ St Georges' Hospital NHS Trust, London, UK.
²⁰ Epsom and St Helier University Hospitals Trust, Carshalton, UK.
²¹ School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Belfast, UK.
²² Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
²³ Kidney and Transplant, Imperial College Healthcare NHS Trust, London, UK.
²⁴ Leeds Teaching Hospitals NHS Trust, Leeds, UK.
²⁵ Central Manchester University Hospitals NHS Trust, Manchester, UK.
²⁶ NHS Lothian, Edinburgh, UK.
²⁷ Division of Medicine, University College London, London, UK.
²⁸ Plymouth Hospitals NHS Trust, Plymouth, UK.
²⁹ The Medical School, Newcastle University Newcastle, Newcastle upon Tyne, UK.
³⁰ Division of Genetics& Molecular Medicine, King's College London, London, UK.
³¹ Barts Health NHS Trust, London, UK.
³² Clinical Transplantation Laboratory at Guy's Hospital, Guy's and St Thomas' NHS Trust, London, UK.
³³ University of Heidelberg, Transplantation Immunology, Heidelberg, Germany.

PMID: 29392897
PMCID: PMC6001640
DOI: 10.1111/ajt.14594

Multicenter Study

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

Maria P Hernandez-Fuentes et al. Am J Transplant. 2018 Jun.

. 2018 Jun;18(6):1370-1379.

doi: 10.1111/ajt.14594. Epub 2018 Feb 1.

Authors

Affiliations

¹ King's College London, MRC Centre for Transplantation, London, UK.
² Welcome Trust Sanger Institute, Human Genetics, Cambridge, UK.
³ Department of Haematology, University of Cambridge, Cambridge, UK.
⁴ NIHR Biomedical Research Centre at Guy's and St Thomas', NHS Foundation Trust and King's College London, London, UK.
⁵ Royal College of Surgeons in Ireland, Dublin, Ireland.
⁶ Renal Institute of Birmingham, Department of Nephrology and Transplantation, Birmingham, UK.
⁷ Nottingham Renal and Transplant Unit, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁸ Transplant and Cellular Immunology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
⁹ Department of Medicine, University of Cambridge, Cambridge, UK.
¹⁰ Leicester General Hospital, Leicester, UK.
¹¹ Transplant Immunology & Immunogenetics, Churchill Hospital, Oxford, UK.
¹² Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹³ Cardiff & Vale University Health Board, Cardiff University, Cardiff, UK.
¹⁴ The Royal Liverpool and Broadgreen University Hospitals, Liverpool, UK.
¹⁵ University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.
¹⁶ School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK.
¹⁷ Beaumont Hospital, Dublin, Ireland.
¹⁸ Queen Alexandra Hospital, Portsmouth, UK.
¹⁹ St Georges' Hospital NHS Trust, London, UK.
²⁰ Epsom and St Helier University Hospitals Trust, Carshalton, UK.
²¹ School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Belfast, UK.
²² Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
²³ Kidney and Transplant, Imperial College Healthcare NHS Trust, London, UK.
²⁴ Leeds Teaching Hospitals NHS Trust, Leeds, UK.
²⁵ Central Manchester University Hospitals NHS Trust, Manchester, UK.
²⁶ NHS Lothian, Edinburgh, UK.
²⁷ Division of Medicine, University College London, London, UK.
²⁸ Plymouth Hospitals NHS Trust, Plymouth, UK.
²⁹ The Medical School, Newcastle University Newcastle, Newcastle upon Tyne, UK.
³⁰ Division of Genetics& Molecular Medicine, King's College London, London, UK.
³¹ Barts Health NHS Trust, London, UK.
³² Clinical Transplantation Laboratory at Guy's Hospital, Guy's and St Thomas' NHS Trust, London, UK.
³³ University of Heidelberg, Transplantation Immunology, Heidelberg, Germany.

PMID: 29392897
PMCID: PMC6001640
DOI: 10.1111/ajt.14594

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.

Keywords: basic (laboratory) research/science; genomics; graft survival; kidney transplantation/nephrology; rejection; translational research/science.

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Figures

**Figure 1**
Analysis workflow and strategy. Main input cohorts, analysis methods, and sample sizes are indicated. For binary traits, numbers indicate samples with/without the trait. For further details, see Methods and Supplementary Methods. GWAS, genome‐wide association studies; WTCCC, Wellcome Trust Case Control Consortium

**Figure 2**
Partitioned heritability analysis of graft survival GWAS results. X‐axis indicates –log10 (P value) for a test for heritability enrichment within 10 cell/tissue‐type categories of genomic annotations, marking tissue‐ or cell‐type‐specific activity. Dotted lines indicate Bonferroni significance level. (A) Death treated as a censored event; (B) death treated as a failure event. CNS, central nervous system

**Figure 3**
Kaplan‐Meier plots of graft survival by number of mismatches by serological typing (A, B, and C), imputed 2‐digit resolution (D, E, and F), and imputed 4‐digit resolution (G, H, and I). P values were obtained from likelihood ratio tests on Cox proportional hazards models

See this image and copyright information in PMC

Comment in

Reply to Hernandez et al. - GWAS of acute renal graft rejection.
Massart A, Ghisdal L, Viklicky O, Naesens M, Abramowicz D, Abramowicz M. Massart A, et al. Am J Transplant. 2018 Aug;18(8):2098-2099. doi: 10.1111/ajt.14877. Epub 2018 May 12. Am J Transplant. 2018. PMID: 29673062 No abstract available.
The genetic determinants of renal allograft rejection.
Hernandez-Fuentes M, Stapleton CP, Cavalleri GL, Conlon P, Weale ME, Lord GM; United Kingdom and Ireland Renal Transplant Consortium (UKIRTC). Hernandez-Fuentes M, et al. Am J Transplant. 2018 Aug;18(8):2100-2101. doi: 10.1111/ajt.14909. Epub 2018 May 28. Am J Transplant. 2018. PMID: 29719114 Free PMC article. No abstract available.

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1. Bradbury L. Annual Report on Kidney Transplantation. Report for 2014/2015. UK: National Health Service ‐ Blood and Transplant; September 2015.
1. Johnson RJ, Bradbury LL, Martin K, Neuberger J, UK Transplant Registry . Organ donation and transplantation in the UK‐the last decade: a report from the UK national transplant registry. Transplantation. 2014;97(Suppl 1):S1‐S27. - PubMed
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1. Nabokow A, Dobronravov VA, Khrabrova M, et al. Long‐term kidney allograft survival in patients with transplant glomerulitis. Transplantation. 2015;99(2):331‐339. - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

Comment in

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

Research Materials