Association of donor small ubiquitin‐like modifier 4 rs237025 genetic variant with tacrolimus elimination in the early period after liver transplantation

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.