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Association of donor small ubiquitin‐like modifier 4 rs237025 genetic variant with tacrolimus elimination in the early period after liver transplantation
Author(s) -
Zhang Tao,
Liu Yuan,
Zeng Rong,
Ling Qi,
Wen Peihao,
Fan Junwei,
Peng Zhihai
Publication year - 2018
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.13597
Subject(s) - tacrolimus , liver transplantation , cyp3a5 , pregnane x receptor , medicine , transplantation , gastroenterology , genotype , pharmacology , biology , gene , genetics , transcription factor , nuclear receptor
Abstract Backgrounds & Aims Individualized tacrolimus treatment can improve drug safety and efficacy. In this study, we aimed to investigate the association of donor and recipient small ubiquitin‐like modifier 4 ( SUMO 4) rs237025 polymorphisms with tacrolimus elimination and the potential mechanism. Methods A total of 297 liver transplant patients were enrolled in the study. CYP 3A5 rs776746 and SUMO 4 rs237025 were genotyped using TaqMan SNP s assays. The activity of nuclear factor‐ kB ( NF ‐ kB ) was evaluated by luciferase assay. The expressions of CYP 3A5 were detected by qRT ‐ PCR and western blotting. Results Tacrolimus C/D ratios was significantly lower for donor SUMO 4 rs237025 AA carriers than AG / GG carriers at weeks 1, 2, 3. In multivariate analysis, donor and recipient CYP 3A5 rs776747, donor SUMO 4 rs237025 and total bilirubin were independent predictors of tacrolimus C/D ratios in the early post‐transplantation period both in Cohort A and Cohort B. When combined donor CYP 3A5 rs776746 and donor SUMO 4 rs237025 genotypes, tacrolimus C/D ratios was highly significant at all investigated time points within the four groups. CYP 3A5 mRNA expression in liver tissues was significantly higher for AA carriers than AG / GG patients under inflammatory stimuli after liver transplantation ( LT ). Furthermore, we demonstrated that SUMO 4 rs237025 G allele could increase NF ‐κB transcriptional activity under inflammatory condition. And activation of NF ‐ kB suppressed the expression of pregnane X receptor ( PXR )‐mediated CYP 3A5 gene. Conclusions Donor SUMO 4 rs237025 genetic variant was associated with higher Tac C/D ratios in the early period after LT , which might be related to the down‐regulation of CYP 3A5 enzyme through the NF ‐ kB signalling pathway.