TY - JOUR
T1 - Donor genetic variants as risk factors for thrombosis after liver transplantation
T2 - A genome-wide association study
AU - Li, Yanni
AU - Nieuwenhuis, Lianne M.
AU - Voskuil, Michiel D.
AU - Gacesa, Ranko
AU - Hu, Shixian
AU - Jansen, Bernadien H.
AU - Venema, Werna T.U.
AU - Hepkema, Bouke G.
AU - Blokzijl, Hans
AU - Verkade, Henkjan J.
AU - Lisman, Ton
AU - Weersma, Rinse K.
AU - Porte, Robert J.
AU - Festen, Eleonora A.M.
AU - de Meijer, Vincent E.
N1 - Publisher Copyright:
© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.
PY - 2021/9
Y1 - 2021/9
N2 - Thrombosis after liver transplantation substantially impairs graft- and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome-wide association study (GWAS) and meta-analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis-susceptible polymorphisms. By performing a meta-GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611-T, p = 4.22 × 10−05) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696-C, p = 2.62 × 10−05) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia-related variants, are associated with increased risk of thrombosis after liver transplantation.
AB - Thrombosis after liver transplantation substantially impairs graft- and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome-wide association study (GWAS) and meta-analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis-susceptible polymorphisms. By performing a meta-GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611-T, p = 4.22 × 10−05) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696-C, p = 2.62 × 10−05) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia-related variants, are associated with increased risk of thrombosis after liver transplantation.
UR - http://www.scopus.com/inward/record.url?scp=85100857992&partnerID=8YFLogxK
U2 - 10.1111/ajt.16490
DO - 10.1111/ajt.16490
M3 - Article
C2 - 33445220
AN - SCOPUS:85100857992
SN - 1600-6135
VL - 21
SP - 3133
EP - 3147
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 9
ER -