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

TY - JOUR

T1 - The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population

AU - The UK Ireland Renal Transplant Consortium

AU - DeKAF Genomics and GEN03 Studies

AU - The International Genetics and Translational Research in Transplantation Network

AU - Stapleton, Caragh P.

AU - Heinzel, Andreas

AU - Guan, Weihua

AU - van der Most, Peter J.

AU - van Setten, Jessica

AU - Lord, Graham M.

AU - Keating, Brendan J.

AU - Israni, Ajay K.

AU - de Borst, Martin H.

AU - Bakker, Stephan J.L.

AU - Snieder, Harold

AU - Weale, Michael E.

AU - Delaney, Florence

AU - Hernandez-Fuentes, Maria P.

AU - Reindl-Schwaighofer, Roman

AU - Oberbauer, Rainer

AU - Jacobson, Pamala A.

AU - Mark, Patrick B.

AU - Chapman, Fiona A.

AU - Phelan, Paul J.

AU - Kennedy, Claire

AU - Sexton, Donal

AU - Murray, Susan

AU - Jardine, Alan

AU - Traynor, Jamie P.

AU - McKnight, Amy Jayne

AU - Maxwell, Alexander P.

AU - Smyth, Laura J.

AU - Oetting, William S.

AU - Matas, Arthur J.

AU - Mannon, Roslyn B.

AU - Schladt, David P.

AU - Iklé, David N.

AU - Cavalleri, Gianpiero L.

AU - Conlon, Peter J.

AU - Franklin, Christopher

AU - Rebollo-Mesa, Irene

AU - Mollon, Jennifer

AU - Perucha, Esperanza

AU - Borrows, Richard

AU - Byrne, Catherine

AU - Clarke, Brendan

AU - Clatworthy, Menna

AU - Feehally, John

AU - Marsh, James

AU - Sheerin, Neil

AU - Solomon, Ellen

AU - Trembath, Richard

AU - Vaughan, Robert

AU - Sacks, Steven H.

N1 - Funding Information: We would like to thank the patients who contributed their DNA and phenotype data, without whom these analyses would not have been possible. C.P.S is supported by the Irish Research Council and Punchestown Kidney Research Fund (grant number EPSPG2015). P.J.P. is supported by an NRS Career Research Fellowship. Further thanks to funding support from Northern Ireland Kidney Research Fund and SFI-DfE (15/IA/3152). TransplantLines is registered at ClinicalTrials.gov with Identifier NCT03272841. The DEKAF and GEN03 studies are supported by 5U19-AI070119 & 5U01-AI058013 from NIAID. The UKIRTC was supported by grants awarded from the Wellcome Trust (090355/A/09/Z, 090355/B/09/Z and 088849/Z/09/Z, ?WTCCC3?), the Medical Research Council (grants G0600698 and MR/J006742/1 to S.H.S.; G0802068 to G.M.L. and MR/K002996/1 to G.M.L; grants G0801537/ID: 88245), Guy's and St Thomas? Charity (grants R080530 and R090782) to M.H.F. and G.M.L., from the European Union FP7 (grant agreement no HEALTH-F5?2010?260687 to M.H.F. and project number 305147: BIO-DrIM to M.H.F. and I.R.M.); and by the National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas? and King's College London. UK and Ireland Renal Transplant Consortium investigators: Maria P. Hernandez-Fuentes, King's College London, MRC Centre for Transplantation, London, UK, UCB Celltech, Slough, UK; Christopher Franklin, Welcome Trust Sanger Institute, Human Genetics, Cambridge, UK; Irene Rebollo-Mesa, King's College London, MRC Centre for Transplantation, London, UK, Jennifer Mollon, King's College London, MRC Centre for Transplantation, London, UK, Department of Haematology, University of Cambridge, Cambridge, UK; Florence Delaney, King's College London, MRC Centre for Transplantation, London, UK, NIHR Biomedical Research Centre at Guy's and St Thomas?, NHS Foundation Trust and King's College London, London, UK; Esperanza Perucha, King's College London, MRC Centre for Transplantation, London, UK; Caragh Stapleton, Royal College of Surgeons in Ireland, Dublin, Ireland; Richard Borrows, Renal Institute of Birmingham, Department of Nephrology and Transplantation, Birmingham, UK; Catherine Byrne, Nottingham Renal and Transplant Unit, Nottingham University Hospitals NHS Trust, Nottingham, UK; Gianpiero Cavalleri, Royal College of Surgeons in Ireland, Dublin, Ireland; Brendan Clarke, Transplant and Cellular Immunology, Leeds Teaching Hospitals NHS Trust, Leeds, UK; Menna Clatworthy, Department of Medicine, University of Cambridge, Cambridge, UK; John Feehally, Leicester General Hospital, Leicester, UK; Susan Fuggle, Transplant Immunology & Immunogenetics, Churchill Hospital, Oxford, UK; Sarah A. Gagliano, Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA; Sian Griffin, Cardiff & Vale University Health Board, Cardiff University, Cardiff, UK; Abdul Hammad, The Royal Liverpool and Broadgreen University Hospitals, Liverpool, UK; Robert Higgins, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK; Alan Jardine, School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK; Mary Keogan, Beaumont Hospital, Dublin, Ireland; Timothy Leach, Queen Alexandra Hospital, Portsmouth, UK; Iain MacPhee, St Georges? Hospital NHS Trust, London, UK; Patrick B. Mark, School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK; James Marsh, Epsom and St Helier University Hospitals Trust, Carshalton, UK; Peter Maxwell, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Belfast, UK; William McKane, Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; Adam McLean, Kidney and Transplant, Imperial College Healthcare NHS Trust, London, UK; Charles Newstead, Leeds Teaching Hospitals NHS Trust, Leeds, UK; Titus Augustine, Central Manchester University Hospitals NHS Trust, Manchester, UK; Paul Phelan, NHS Lothian, Edinburgh, UK; Steve Powis, Division of Medicine, University College London, London, UK; Peter Rowe, Plymouth Hospitals NHS Trust, Plymouth, UK; Neil Sheerin, The Medical School, Newcastle University Newcastle, Newcastle upon Tyne, UK; Ellen Solomon, Division of Genetics & Molecular Medicine, King's College London, London, UK; Henry Stephens, NHS Lothian, Edinburgh, UK; Raj Thuraisingham, Barts Health NHS Trust, London, UK; Richard Trembath, Division of Genetics & Molecular Medicine, King's College London, London, UK; Peter Topham, Leicester General Hospital, Leicester, UK; Robert Vaughan, Clinical Transplantation Laboratory at Guy's Hospital, Guy's and St Thomas? NHS Trust, London, UK; Steven H. Sacks, King's College London, MRC Centre for Transplantation, London, UK, NIHR Biomedical Research Centre at Guy's and St Thomas?, NHS Foundation Trust and King's College London, London, UK; Peter Conlon, Royal College of Surgeons in Ireland, Dublin, Ireland, Beaumont Hospital, Dublin, Ireland; Gerhard Opelz, University of Heidelberg, Transplantation Immunology, Heidelberg, Germany; Nicole Soranzo, Welcome Trust Sanger Institute, Human Genetics, Cambridge, UK, Department of Haematology, University of Cambridge, Cambridge, UK; Michael E. Weale, Division of Genetics & Molecular Medicine, King's College London, London, UK, Genomics plc, Oxford, UK; Graham M. Lord, King's College London, MRC Centre for Transplantation, London, UK, NIHR Biomedical Research Centre at Guy's and St Thomas?, NHS Foundation Trust and King's College London, London, UK, Faculty of Biology, Medicine and Health, University of Manchester, UK. Deterioration of Kidney Allograft Function Genomics and Genomics of Kidney Transplantation investigators: Arthur Matas, MD, Department of Surgery, University of Minnesota, Minneapolis, MN; J. Michael Cecka, MD, UCLA Immunogenetics Center, Los Angeles, CA; John Connett, PhD, Division of Biostatistics, University of Minnesota, Minneapolis, MN; Fernando G. Cosio, MD, Division of Nephrology, Mayo Clinic, Rochester, MN; Robert Gaston, MD, Division of Nephrology, University of Alabama, Division of Nephrology, Birmingham, AL; Rosalyn Mannon, MD, Division of Nephrology, University of Alabama, Division of Nephrology, Birmingham, AL; Sita Gourishankar, MD, Division of Nephrology and Immunology, University of Alberta, Edmonton, Alberta, Canada; Joseph P. Grande, MD, PhD, Mayo Clinic College of Medicine, Rochester, MN; Lawrence Hunsicker, MD, Nephrology Division, Iowa City, IA; Bertram Kasiske, MD, Division of Nephrology, Hennepin County Medical Center, Minneapolis, MN; and David Rush, MD, Health Sciences Center, Winnipeg MB. Publisher Copyright: © 2019 The American Society of Transplantation and the American Society of Transplant Surgeons

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Genetic variation across the human leukocyte antigen loci is known to influence renal-transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFR at different time-points, out to 5 years posttransplantation. We conducted GWAS meta-analyses across 10 844 donors and recipients from five European ancestry cohorts. We also analyzed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with nontransplant eGFR, on posttransplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1-year posttransplant. Thirty-two percent of the variability in eGFR at 1-year posttransplant was explained by our model containing clinical covariates (including weights for death/graft-failure), principal components and combined donor-recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR posttransplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a posttransplant context. Despite PRS being a significant predictor of eGFR posttransplant, the effect size of common genetic factors is limited compared to clinical variables.

AB - Genetic variation across the human leukocyte antigen loci is known to influence renal-transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFR at different time-points, out to 5 years posttransplantation. We conducted GWAS meta-analyses across 10 844 donors and recipients from five European ancestry cohorts. We also analyzed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with nontransplant eGFR, on posttransplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1-year posttransplant. Thirty-two percent of the variability in eGFR at 1-year posttransplant was explained by our model containing clinical covariates (including weights for death/graft-failure), principal components and combined donor-recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR posttransplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a posttransplant context. Despite PRS being a significant predictor of eGFR posttransplant, the effect size of common genetic factors is limited compared to clinical variables.

KW - basic (laboratory) research/science

KW - clinical research/practice

KW - genetics

KW - genomics

KW - glomerular filtration rate (GFR)

KW - kidney transplantation/nephrology

KW - microarray/gene array

KW - molecular biology: DNA

UR - http://www.scopus.com/inward/record.url?scp=85064888192&partnerID=8YFLogxK

U2 - 10.1111/ajt.15326

DO - 10.1111/ajt.15326

M3 - Article

C2 - 30920136

AN - SCOPUS:85064888192

SN - 1600-6135

VL - 19

SP - 2262

EP - 2273

JO - American Journal of Transplantation

JF - American Journal of Transplantation

IS - 8

ER -