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

Yanni Li, Lianne M. Nieuwenhuis, Michiel D. Voskuil, Ranko Gacesa, Shixian Hu, Bernadien H. Jansen, Werna T.U. Venema, Bouke G. Hepkema, Hans Blokzijl, Henkjan J. Verkade, Ton Lisman, Rinse K. Weersma, Robert J. Porte, Eleonora A.M. Festen*, Vincent E. de Meijer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3133-3147
Number of pages15
JournalAmerican Journal of Transplantation
Volume21
Issue number9
DOIs
Publication statusPublished - Sept 2021
Externally publishedYes

Bibliographical note

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.

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