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Meta-Analysis
. 2024 Dec 11;9(1):e0601.
doi: 10.1097/HC9.0000000000000601. eCollection 2025 Jan 1.

Genome-wide meta-analysis associates donor-recipient non-HLA genetic mismatch with acute cellular rejection post-liver transplantation

Lianne M Nieuwenhuis  1   2 , Yanni Li  2   3 , Bao-Li Loza  4 , Annechien J A Lambeck  5 , Shixian Hu  2   3 , Ranko Gacesa  2   3 , Michiel D Voskuil  2   3 , Bouke G Hepkema  5 , Bernadien H Jansen  2 , Hans Blokzijl  2 , Henk-Jan Verkade  6 , Marius C van den Heuvel  7 , Sumeet Asrani  8 , Giuliano Testa  8 , Goran Klintmalm  8 , James Trotter  8 , Kim M Olthoff  4 , Abraham Shaked  4 , Brendan J Keating  4 , Rinse K Weersma  2 , Eleonora A M Festen  2   3 , Vincent E de Meijer  1 ; TransplantLines Investigators
Collaborators, Affiliations
Meta-Analysis

Genome-wide meta-analysis associates donor-recipient non-HLA genetic mismatch with acute cellular rejection post-liver transplantation

Lianne M Nieuwenhuis et al. Hepatol Commun. .

Abstract

Background: Acute cellular rejection (ACR) remains a common complication causing significant morbidity post-liver transplantation. Non-human leukocyte antigen (non-HLA) mismatches were associated with an increased risk of ACR in kidney transplantation. Therefore, we hypothesized that donor-recipient non-HLA genetic mismatch is associated with increased ACR incidence post-liver transplantation.

Methods: We conducted an international multicenter case-control genome-wide association study of donor-recipient liver transplant pairs in 3 independent cohorts, totaling 1846 pairs. To assess genetic mismatch burden, we calculated sum scores for single-nucleotide polymorphism (SNP) mismatch based on all non-HLA functional SNPs, specifically SNPs coding for transmembrane or secreted proteins as they more likely affect the immune system. We analyzed the association between the non-HLA mismatch scores and ACR in a multivariable Cox regression model per cohort, followed by a weighted meta-analysis.

Results: During the first year post-transplantation, 90 of 689 (13%), 161 of 720 (22%), and 48 of 437 (11%) recipients experienced ACR in cohorts 1-3, respectively. Weighted meta-analyses showed that higher mismatch in functional non-HLA SNPs was associated with an increased incidence of ACR (HR 5.99; 95% CI: 1.39-20.08; p=0.011). Moreover, we found a larger effect of mismatch in SNPs coding for transmembrane or secreted proteins on ACR (HR 7.54; 95% CI 1.95-28.79; p=0.003). Sensitivity analyses showed that imputed HLA mismatch did not affect the associations between both non-HLA mismatch scores and ACR.

Conclusions: Donor-recipient mismatch of functional non-HLA SNPs overall and, especially, of SNPs encoding transmembrane or secreted proteins correlated with 1-year ACR post-liver transplantation. Identifying high-risk immunological burdens between pairs may prevent early graft rejection and aid in personalizing immunosuppressive therapy. Future studies are, however, needed to validate our findings using a genotyped HLA cohort.

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Conflict of interest statement

Vincent E. de Meijer reports a VENI research grant by the Dutch Research Council (NWO; grant #09150161810030), a Research grant from the Dutch Ministry of Economic Affairs (Health~Holland Public Private Partnership grant #PPP-2019-024), and a Research grant from the Dutch Society for Gastroenterology (NVGE #01-2021), all outside the submitted work. Eleonora A. M. Festen is supported by a Clinical Fellow grant from the Dutch Research Council (NWO; grant #90719075) and a Research grant from the Dutch Ministry of Economics. Hans Blokzijl received grants from Abbvie. Henkjan Verkade is on the speaker’s bureau, and received grants from Albireo/ Ipsen. He consults and received grants from Mirum. He consults for Orphalan and Vertex. He is on the speaker’s bureau for Astellas. Rinse Weersma consults and received grants from Takeda Pharmaceuticals. He is on the speaker’s bureau for Abbvie and Ferring. He received grants from Johnson and Johnson. Eleonora Festen received grants from Takeda. The remaining authors have no conflicts to report.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
Flowchart of data management. (A) Inclusion of donor-recipient pairs after genotyping quality control. (B) Quality control, imputation, and non-HLA functional SNP selection from SNPs genotyped by Global Screening Array-24 v1.0 (Illumina, San Diego, CA) and Affymetrix Axiom Transplant Arrays. (C) The non-HLA SNP mismatch score is calculated by comparing allele overlap between the donor and recipient for each functional variant. Abbreviations: GSA, Global Screening Array; HLA, human leukocyte antigen; LT, liver transplantation; SNP, single-nucleotide polymorphism.
FIGURE 2
FIGURE 2
Forest plot depicting the results of regression analyses for acute T-cell-mediated cellular rejection, presented for individual cohorts as well combined using a meta-analysis. This graph depicts for each cohort the results of the associations found with acute T-cell mediated cellular rejection in a proportional hazard Cox regression model for (A) overall functional non–human leukocyte antigen mismatch score and (B) mismatch in single-nucleotide polymorphisms coding for transmembrane or secreted proteins. The top line in both panels shows the results of the meta-analysis of all 3 cohorts, with individual cohorts as random effects.
FIGURE 3
FIGURE 3
Forest plot depicting 5-year graft survival Cox regression analyses results of individual cohorts and all combined using a meta-analysis. This graph depicts for each cohort the results of the associations found with 5-year graft survival in a proportional hazard Cox regression model for (A) overall functional non–human leukocyte antigen mismatch score, and (B) mismatch in single-nucleotide polymorphisms coding for transmembrane or secreted proteins. The top line in both panels shows the results of the meta-analysis of all 3 cohorts, with individual cohorts as random effects.
FIGURE 4
FIGURE 4
Forest plot depicting the results of human leukocyte antigen mismatch-corrected Cox regression analyses for acute T-cell mediated cellular rejection and 5-year graft survival, shown for individual cohorts and combined through a meta-analysis. This graph depicts for each cohort the results of the associations found with acute T-cell mediated cellular rejection (A and B) and 5-year graft survival (C and D) in a proportional hazard Cox regression model for overall functional non–human leukocyte antigen mismatch score (A and C), and mismatch in SNPs coding for transmembrane or secreted proteins (B and D). The top line in both panels shows the results of the meta-analysis of all 3 cohorts, with individual cohorts as random effects.
See this image and copyright information in PMC

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