Donor genetic variants as risk factors for thrombosis after liver transplantation: A genome‐wide association study

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...

Full description

Saved in:
Bibliographic Details
Published in:American journal of transplantation 2021-09, Vol.21 (9), p.3133-3147
Main Authors: Li, Yanni, Nieuwenhuis, Lianne M., Voskuil, Michiel D., Gacesa, Ranko, Hu, Shixian, Jansen, Bernadien H., Venema, Werna T. U., Hepkema, Bouke G., Blokzijl, Hans, Verkade, Henkjan J., Lisman, Ton, Weersma, Rinse K., Porte, Robert J., Festen, Eleonora A. M., Meijer, Vincent E.
Format: Article
Language:English
Subjects:
Adult
Child
donors and donation
Genetic diversity
genetics
Genome-wide association studies
Genome-Wide Association Study
Genomes
Graft Survival
Humans
Liver
liver disease
Liver diseases
Liver transplantation
Liver Transplantation - adverse effects
liver transplantation/hepatology
Liver transplants
Living Donors
microarray/gene array
Organ donors
Original
ORIGINAL ARTICLES
Pediatrics
Retrospective Studies
Risk Factors
Thromboembolism
Thrombophilia
Thrombosis
Thrombosis - genetics
thrombosis and thromboembolism
Tissue Donors
TOR protein
translational research/science
vascularized composite and reconstructive transplantation
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. A meta‐analysis of two genome‐wide association studies of adult and pediatric liver transplants identifies three common candidate risk loci in the donor, but not previously known thrombophilia‐related variants, were newly associated with increased risk of thrombosis after liver transplantation.
ISSN:1600-6135
1600-6143
DOI:10.1111/ajt.16490