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 (SUMO4) rs237025 polymorphisms with tacrolimus elimination and the potential mechanism.

Methods: A total of 297 liver transplant patients were enrolled in the study. CYP3A5 rs776746 and SUMO4 rs237025 were genotyped using TaqMan SNPs assays. The activity of nuclear factor-kB (NF-kB) was evaluated by luciferase assay. The expressions of CYP3A5 were detected by qRT-PCR and western blotting.

Results: Tacrolimus C/D ratios was significantly lower for donor SUMO4 rs237025 AA carriers than AG/GG carriers at weeks 1, 2, 3. In multivariate analysis, donor and recipient CYP3A5 rs776747, donor SUMO4 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 CYP3A5 rs776746 and donor SUMO4 rs237025 genotypes, tacrolimus C/D ratios was highly significant at all investigated time points within the four groups. CYP3A5 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 SUMO4 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 CYP3A5 gene.

Conclusions: Donor SUMO4 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 CYP3A5 enzyme through the NF-kB signalling pathway.