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

Zhang, Tao; Liu, Yuan; Zeng, Rong; Ling, Qi; Fan, Junwei; Peng, Zhihai

doi:10.1111/liv.13597

Cited by 11 publications

(12 citation statements)

References 34 publications

(52 reference statements)

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“…The incorporated cofactors were comprised of donor and recipient CYP3A5 rs776746 genotypes, TLR9 rs352139 genotype, Hb, ALT, AST, TBIL, DBIL, Alb, Cr, and urea. Consistent with previous findings, 19 tacrolimus C/D ratios were significantly predicted by donor and recipient CYP3A5 rs776746 genotypes at every week. Notably, donor TLR9 rs352139 polymorphism was also identified as an independent predictor of C/D ratios for weeks 1, 2, and 3 (Table 3).…”

Section: Multivariate Analysis For Factors Affecting Tacrolimus Pharmsupporting

confidence: 91%

“…The CYP3A5 rs776746 polymorphism remained the underlying factor explaining the interindividual variation of tacrolimus clearance, which has been confirmed in our cohort previously. 19 Of note, combined donor CYP3A5 rs776746 and donor TLR9 rs352139 genotypes showed an increased significance of the observed effects on pharmacokinetics compared with CYP3A5 genotype alone. Tacrolimus C/D ratios were influenced significantly by the TLR9 and CYP3A5 combined genotype.…”

Section: Discussionmentioning

confidence: 92%

“…Exclusion criteria were (i) multiorgan transplant patients, (ii) follow‐up time of no more than 1 month, and (iii) incomplete patient medical records. The patient characteristics were previously described . An initial dosage of tacrolimus (0.06 mg/kg/day) was administered orally twice daily.…”

Section: Methodsmentioning

confidence: 99%

“…Two independent cohorts including 297 patients receiving orthotopic LT between January 2012 and December 2016 were enrolled. 19 Cohort A comprised patients recruited from Shanghai General Hospital of Shanghai Jiao Tong University (n = 115) and the First Affiliated Hospital of Zhengzhou University (n = 85). Cohort B (validation set) comprised 97 patients from the First Affiliated Hospital, Zhejiang University School of Medicine.…”

Section: Patients and Study Designmentioning

confidence: 99%

“…The patient characteristics were previously described. 19 An initial dosage of tacrolimus (0.06 mg/kg/day) was administered orally twice daily. Therapeutic drug monitoring was performed routinely after LT.…”

Section: Patients and Study Designmentioning

confidence: 99%

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

Liu

Zhang

et al. 2019

Pharmacotherapy

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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.

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Section: Multivariate Analysis For Factors Affecting Tacrolimus Pharmsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Patients and Study Designmentioning

confidence: 99%

Section: Patients and Study Designmentioning

confidence: 99%

See 3 more Smart Citations

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

Liu

Zhang

et al. 2019

Pharmacotherapy

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The influence of recipient SLCO1B1 rs2291075 polymorphism on tacrolimus dose–corrected trough concentration in the early period after liver transplantation

Fang

Wang

et al. 2021

Eur J Clin Pharmacol

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Purpose To explore the relationship between rs2291075 polymorphism in SLCO1B1 gene, which encodes an influx transmembrane protein transporter, and tacrolimus dose–corrected trough concentration (C/D, ng ml−1 mg−1 kg−1) in the early period after liver transplantation. Methods CYP3A5 rs776746 and SLCO1B1 rs2291075 polymorphisms of 210 liver transplantation patients and their corresponding donor livers were assessed by PCR amplification and DNA sequencing. The influence of gene polymorphisms on C/D values of tacrolimus was analyzed. The early postoperative period after liver transplantation was divided into the convalescence phase (1–14 days) and stationary phase (15–28 days) according to the change of liver function and tacrolimus C/D values. Results The combined analysis of donor and recipient CYP3A5 rs776746 could distinguish the metabolic phenotype of tacrolimus into three groups: fast elimination (FE), intermediate elimination (IE), and slow elimination (SE), which was entitled the FIS classification system. Tacrolimus C/D ratios of recipient SLCO1B1 rs2291075 CT and TT carriers were very close and were significantly lower than those of recipient SLCO1B1 rs2291075 CC genotype carriers in convalescence phase (p = 0.0195) and in stationary phase (p = 0.0152). There were no statistically significant differences between tacrolimus C/D ratios of patients carried with SLCO1B1 rs2291075 CT, TT genotype donors, and those carried with SLCO1B1 rs2291075 CC genotype donors. A model consisting of tacrolimus daily dose, total bilirubin, FIS classification, and recipient SLCO1B1 rs2291075 could predict tacrolimus C/D ratios in the convalescence phase by multivariate analysis. However, recipient SLCO1B1 rs2291075 genotype failed to enter forecast model for C/D ratios in stationary phase. Recipient SLCO1B1 rs2291075 genotype had significant effect on tacrolimus C/D ratios in convalescence phase (p = 0.0300) and stationary phase (p = 0.0400) in subgroup, which excluded the interference come from donor and recipient CYP3A5 rs776746. Conclusion SLCO1B1 rs2291075 could be a novel genetic locus associated with tacrolimus metabolism. The combined analysis of donor and recipient CYP3A5 rs776746, recipient SLCO1B1 rs2291075 genotypes, could be helpful to guide the personalized administration of tacrolimus in early period after liver transplantation.

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Dosage Optimization Based on Population Pharmacokinetic Analysis of Tacrolimus in Chinese Patients with Nephrotic Syndrome

Zhu

et al. 2019

Pharm Res

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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

Abstract: 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.

Cited by 11 publications

References 34 publications

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

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

The influence of recipient SLCO1B1 rs2291075 polymorphism on tacrolimus dose–corrected trough concentration in the early period after liver transplantation

Dosage Optimization Based on Population Pharmacokinetic Analysis of Tacrolimus in Chinese Patients with Nephrotic Syndrome

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