全基因组荟萃分析表明，供体-受体非人类白细胞抗原（HLA）基因错配与肝移植后急性细胞排斥反应相关。
Genome-wide meta-analysis associates donor-recipient non-HLA genetic mismatch with acute cellular rejection post-liver transplantation.
作者信息
Nieuwenhuis Lianne M, Li Yanni, Loza Bao-Li, Lambeck Annechien J A, Hu Shixian, Gacesa Ranko, Voskuil Michiel D, Hepkema Bouke G, Jansen Bernadien H, Blokzijl Hans, Verkade Henk-Jan, van den Heuvel Marius C, Asrani Sumeet, Testa Giuliano, Klintmalm Goran, Trotter James, Olthoff Kim M, Shaked Abraham, Keating Brendan J, Weersma Rinse K, Festen Eleonora A M, de Meijer Vincent E
机构信息
Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
出版信息
Hepatol Commun. 2024 Dec 11;9(1). doi: 10.1097/HC9.0000000000000601. eCollection 2025 Jan 1.
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.
背景
急性细胞排斥反应（ACR）仍是肝移植后导致显著发病的常见并发症。非人类白细胞抗原（non-HLA）错配与肾移植中ACR风险增加相关。因此，我们推测供体-受体非HLA基因错配与肝移植后ACR发生率增加相关。
方法
我们在3个独立队列中对供体-受体肝移植对进行了一项国际多中心病例对照全基因组关联研究，共1846对。为评估基因错配负担，我们基于所有非HLA功能性单核苷酸多态性（SNP）计算SNP错配的总和分数，特别是编码跨膜或分泌蛋白的SNP，因为它们更可能影响免疫系统。我们在每个队列的多变量Cox回归模型中分析非HLA错配分数与ACR之间的关联，随后进行加权荟萃分析。
结果
在移植后的第一年，队列1-3中分别有689名受者中的90名（13%）、720名受者中的161名（22%）和437名受者中的48名（11%）发生了ACR。加权荟萃分析表明，功能性非HLA SNP中较高的错配与ACR发生率增加相关（风险比5.99；95%置信区间：1.39-20.08；p=0.011）。此外，我们发现编码跨膜或分泌蛋白的SNP错配对ACR的影响更大（风险比7.54；95%置信区间1.95-28.79；p=0.003）。敏感性分析表明，推算的HLA错配不影响非HLA错配分数与ACR之间的关联。
结论
供体-受体功能性非HLA SNP总体上，尤其是编码跨膜或分泌蛋白的SNP错配与肝移植后1年ACR相关。识别配对之间的高风险免疫负担可能预防早期移植物排斥，并有助于免疫抑制治疗的个性化。然而，未来需要使用基因分型的HLA队列来验证我们的发现。
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