1. Donor genetic variants as risk factors for thrombosis after liver transplantation
- Author
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Werna T. Uniken Venema, Bernadien H. Jansen, Bouke G. Hepkema, Hans Blokzijl, Robert J. Porte, Ton Lisman, Henkjan J. Verkade, Rinse K. Weersma, Eleonora A. M. Festen, Yanni Li, Ranko Gacesa, Lianne M Nieuwenhuis, Shixian Hu, Michiel Voskuil, Vincent E de Meijer, Center for Liver, Digestive and Metabolic Diseases (CLDM), Lifestyle Medicine (LM), Groningen Institute for Organ Transplantation (GIOT), and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
- Subjects
Adult ,Candidate gene ,medicine.medical_specialty ,translational research/science ,donors and donation ,medicine.medical_treatment ,vascularized composite and reconstructive transplantation ,thrombosis and thromboembolism ,Genome-wide association study ,030230 surgery ,Liver transplantation ,Thrombophilia ,Bioinformatics ,03 medical and health sciences ,Liver disease ,gene array ,0302 clinical medicine ,microarray/gene array ,Risk Factors ,Internal medicine ,medicine ,Living Donors ,Immunology and Allergy ,Humans ,Pharmacology (medical) ,genetics ,Child ,science ,Retrospective Studies ,Transplantation ,liver transplantation ,business.industry ,Graft Survival ,Thrombosis ,Hepatology ,Clinical Science ,medicine.disease ,Tissue Donors ,translational research ,hepatology ,Original Article ,ORIGINAL ARTICLES ,business ,liver disease ,liver transplantation/hepatology ,microarray ,Genome-Wide Association Study - Abstract
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.
- Published
- 2021
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