TLR9 rs352139 Genetic Variant Promotes Tacrolimus Elimination in Chinese Liver Transplant Patients During the Early Posttransplantation Period

There are limited markers that could facilitate individualized tacrolimus treatment in the early posttransplantation period. Genetic factors have been found to play critical roles in determining tacrolimus pharmacokinetics.

Donor TLR9 rs352139 genetic variant facilitated tacrolimus elimination during the early stage after LT in Chinese patients, which might be related to the upregulation of CYP3A5 enzyme via the NF-kB/PXR signaling pathway.

Two independent cohorts including 297 patients receiving liver transplantation (LT) were enrolled in this study (cohort A was composed of 200 patients; cohort B included 97 patients and served as a validation set). Toll-like receptors polymorphisms were genotyped using TaqMan single nucleotide polymorphisms (SNPs) assays. The protein expressions were detected by Western blotting. The metabolism assay was used to quantify tacrolimus elimination. The activity of nuclear factor-kB (NF-kB) was evaluated by luciferase reporter assay.

We aimed to examine the association of donor and recipient Toll-like receptor (TLR) polymorphisms with tacrolimus elimination and the potential mechanism for TLR gene polymorphism-mediated tacrolimus metabolism.

Tacrolimus dose-adjusted trough blood concentrations (C/D) ratios were significantly lower for donor TLR9 rs352139 AG/GG carriers than AA carriers at weeks 1, 2, and 3 after LT. In multivariate analysis, donor and recipient CYP3A5 rs776746 and donor TLR9 rs352139 were independent predictors of tacrolimus C/D ratios in the early period after transplantation in both cohorts. When investigating the combined effects of donor CYP3A5 rs776746 and donor TLR9 rs352139 genotypes, the C/D ratios were remarkably significant at all time points during the first month after LT within the four groups. Furthermore, CYP3A5 mRNA expression in liver tissue was significantly higher for AG/GG patients than AA carriers after LT. In addition, we demonstrated that the TLR9 rs352139 genetic variant promotes tacrolimus metabolism of liver cells via upregulation of CYP3A5, which is dependent on the repression of NF-κB/pregnane X receptor (PXR) signaling. Conclusions: Donor TLR9 rs352139 genetic variant facilitated tacrolimus elimination during the early stage after LT in Chinese patients, which might be related to the upregulation of CYP3A5 enzyme via the NF-kB/PXR signaling pathway.

ClinicalTrials.gov NCT02752529.