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 - Fuggle, Susan
AU - Gagliano, Sarah A.
AU - Griffin, Sian
AU - Hammad, Abdul
AU - Higgins, Robert
AU - Keogan, Mary
N1 - Publisher Copyright:
© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons
PY - 2019/8
Y1 - 2019/8
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
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UR - http://www.scopus.com/inward/citedby.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 -