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

Abstract

Background 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. Objective 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. Methods 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. Results 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.

Distinct Effects of Inflammation on Cytochrome P450 Regulation and Drug Metabolism: Lessons from Experimental Models and a Potential Role for Pharmacogenetics

“…TLR9-rs352139 AA genotype carriers were thus protected from the effects of ischemia-reperfusion-induced inflammation, which resulted in conservation of their metabolic capacity. The opposite effect was observed for carriers of the TLR4-rs1927907-GG phenotype who exhibited higher tacrolimus C/D ratios than AA/AG carriers, indicating that these patients were more susceptible to the effects of inflammation on their drug-metabolizing capacity [91,92]. These studies illustrate that genetic variants in receptors can be important modulators of inflammation, which may be particularly relevant for receptors (e.g., IL6R or IL-1R) that are directly involved in the downregulation of CYP enzymes, but this remains to be investigated.…”

“…Therefore, it has been postulated that genetic variability in TLRs may alter the effect of inflammation and its consequences for drug metabolism. Ou et al showed that liver transplant patients with the TLR9-rs352139 AA genotype exhibited lower C/D tacrolimus levels than carriers of the AG/GG genotype [91]. Subsequent cellular experiments provided functional support for these observations and demonstrated that the TLR9-rs352139 variant impaired TLR9 expression and consequently reduced NF-κB activation.…”

Genotype-guided model significantly improves accuracy of tacrolimus initial dosing after liver transplantation

“… 11 , 12 Enzymes in the cytochrome P450 (CYP) 3A family are responsible for the oxidative metabolism of tacrolimus. 13 Numerous studies have demonstrated the importance of the genetic variation (rs776746, or ∗3) of CYP3A5 gene in tacrolimus metabolism. 14 , 15 Recent guidelines for the use of tacrolimus proposed by the Clinical Pharmacogenetics Implementation Consortium (CPIC) provide preliminary suggestions relevant to the rs776746 genotype and tacrolimus dosing.…”