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            Rs5744247 Polymorphism as a New Biomarker of Tacrolimus Elimination in Chinese Liver Transplant Patients During the Early Post-Transplantation Period: Results from Two Cohort Studies

Fan, Junwei; Zhang, Xiaoqing; Ren, Lei; Chen, Fan; Wu, Shaohan; Guo, Feng; Qin, Shengying; Wang, Zhaowen; Zhong, Lin; Xing, Tonghai; Sun, Xiaojiang; Peng, Zhihai

doi:10.2217/pgs.14.166

Cited by 16 publications

(15 citation statements)

References 45 publications

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“…Previous studies have reported genetic associations of IL-2, IL-4 and IL-6 with blood concentrations of calcineurin inhibitors [21] . Genetic polymorphisms in IL-18 (eg, rs5744247) and IL-10 (eg, -819 C/T and -592 C/A) can also affect TAC dose requirements [37,38] . However, the exact mechanism by which these polymorphisms affect TAC dose requirements is unknown.…”

Section: Discussionmentioning

confidence: 99%

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

Liu

Zhang

et al. 2017

Acta Pharmacol Sin

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The highly variable pharmacokinetics and narrow therapeutic window of tacrolimus (TAC) has hampered its clinical use. Genetic polymorphisms may contribute to the variable response, but the evidence is not compelling, and the explanation is unclear. In this study we attempted to find previously unknown genetic factors that may influence the TAC dose requirements. The association of 105 pathway-related single nucleotide polymorphisms (SNPs) with TAC dose-adjusted concentrations (C0/D) was examined at 7, 30 and 90 d post-operation in 382 Chinese kidney transplant recipients. In CYP3A5 non-expressers, the patients carrying the IL-3 rs181781 AA genotype showed a significantly higher TAC logC0/D than those with the AG genotype at 30 and 90 d post-operation (AA vs AG, 2.21±0.06 vs 2.01±0.03, P=0.004; and 2.17±0.06 vs 2.03±0.03, P=0.033, respectively), and than those with the GG genotype at 30 d (AA vs GG, 2.21±0.06 vs 2.04±0.03, P=0.011). At 30 d, the TAC logC0/D in the grouped AG+GG genotypes of CTLA4 rs4553808 was significantly lower than that in the AA genotype (P=0.041) in CYP3A5 expressers, but it was higher (P=0.008) in the non-expressers. We further validated the influence of CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437 on the TAC C0/D; other candidate SNPs were not associated with the differences in TAC C0/D. In conclusion, genetic polymorphisms in the immune genes IL-3 rs181781 and CTLA4 rs4553808 may influence the TAC C0/D. They may, together with CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437, contribute to the variation in TAC dose requirements. When conducting individualized therapy with tacrolimus, these genetic factors should be taken into account.

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Section: Discussionmentioning

confidence: 99%

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

Liu

Zhang

et al. 2017

Acta Pharmacol Sin

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“…In the current study, researchers investigated the associations of CYP3A5, interleukin (IL)-6, IL-10, and IL-18 genetic polymorphisms with tacrolimus metabolism. [456] Based on our findings, we propose the existence of a gene interaction network that affects tacrolimus pharmacogenomics in patients with HCC after OLT.…”

Section: Discussionmentioning

confidence: 77%

“…Previous studies suggested that some gene polymorphisms are associated with drug metabolism. [456] Pharmacogenomics focuses on the relationship between host genetics and drug metabolism. Most previous studies focused on pharmacogenomics regardless of pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Gene Variations of Sixth Complement Component Affecting Tacrolimus Metabolism in Patients with Liver Transplantation for Hepatocellular Carcinoma

Liao

et al. 2017

Chinese Medical Journal

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Background:Orthotopic liver transplantation (OLT) improves the prognosis of patients with hepatocellular carcinoma (HCC). Moreover, the complement system is a powerful immune effector that can affect liver function and process of liver cirrhosis. However, studies correlating the complement system with tacrolimus metabolism after OLT are scarce. In this study, the role of single nucleotide polymorphisms (SNPs) associated with the sixth complement component (C6) in tacrolimus metabolism was investigated during the early stages of liver transplantation.Methods:The study enrolled 135 adult patients treated with OLT for HCC between August 2011 and October 2013. Ten SNPs in C6 gene and rs776746 in cytochrome P450 3A5 (CYP3A5) gene were investigated. The tacrolimus levels were monitored daily during 4 weeks after transplantation.Results:Both donor and recipient CYP3A5 rs776746 allele A were correlated with decreased concentration/dose (C/D) ratios. Recipient C6 rs9200 allele G and donor C6 rs10052999 homozygotes were correlated with lower C/D ratios. Recipient CYP3A5 rs776746 allele A (yielded median tacrolimus C/D ratios of 225.90 at week 1 and 123.61 at week 2), C6 rs9200 allele G (exhibited median tacrolimus C/D ratios of 211.31 at week 1, 110.23 at week 2, and 99.88 at week 3), and donor CYP3A5 rs776746 allele A (exhibited median C/D ratios of 210.82 at week 1, 111.06 at week 2, 77.49 at week 3, and 85.60 at week 4) and C6 rs10052999 homozygote (exhibited median C/D ratios of 167.59 at week 2, 157.99 at week 3, and 155.36 at week 4) were associated with rapid tacrolimus metabolism. With increasing number of these alleles, patients were found to have lower tacrolimus C/D ratios at various time points during the 4 weeks after transplantation. In multiple linear regression analysis, recipient C6 rs9200 group (AA vs. GG/GA) was found to be related to tacrolimus metabolism at weeks 1, 2, and 3 (P = 0.005, P = 0.045, and P = 0.033, respectively), whereas donor C6 rs10052999 group (CC/TT vs. TC) was demonstrated to be correlated with tacrolimus metabolism only at week 4 (P = 0.001).Conclusions:Recipient C6 gene rs9200 polymorphism and donor C6 gene rs10052999 polymorphism are new genetic loci that affect tacrolimus metabolism in patients with HCC after OLT.

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“…Two parameters were checked as confounders, and apart from five studies, others did not assess one or both of them. Appraisal of outcomes revealed that in 23 studies, outcomes of interest were not presented (eg, because of nonsignificant data) or presented improperly (eg, as median) which led to the exclusion of the study from the analyses or obligated us to estimate required data . Eight studies did not continue blood level measurement at specified time points for at least one month or did not mention the time of measurement clearly .…”

Section: Resultsmentioning

confidence: 99%

Effect of CYP3A5*1 expression on tacrolimus required dose after liver transplantation: A systematic review and meta‐analysis

Hendijani

Azarpira

Kaviani

2018

Clinical Transplantation

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We systematically collected eligible data to measure the effect of CYP3A5*1 expression on personalized tacrolimus therapy. Six databases were searched for studies on adult liver transplant recipients and donors of liver graft which reported tacrolimus dose requirement, trough blood concentration, and/or concentration/dose (C/D) ratio in expressers and nonexpressers of CYP3A5*1. Eligible data were pooled by meta-analysis. Sixteen observational studies (1309 recipients, 1044 donors of liver graft) were included in the analyses. Tacrolimus C/D ratio was lower, and the dose was higher in recipient expressers of CYP3A5*1 and/or carriers of expresser liver graft at 1-4 weeks and 2-4, 6, and 12 months post-transplantation. Tacrolimus blood concentration was lower at the first two weeks. Pair expressers were affected by about twofold, and the effect was different between ethnic groups. CYP3A5*1 expression in recipients increased tacrolimus required dose by 0.023 at first, 0.022 at third, and 0.012 mg/kg/day at sixth month. Its expression in graft tissue increased tacrolimus required dose by 0.024 at first, 0.035 at third, and 0.032 mg/kg/day at sixth month. Considering CYP3A5*1 polymorphism can be helpful in individualization of tacrolimus efficient dose prior to administration, and it can remove initial high-risk lag time (over/underdose period before reaching target blood level) at first few days post-transplantation.

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Donor IL-18 Rs5744247 Polymorphism as a New Biomarker of Tacrolimus Elimination in Chinese Liver Transplant Patients During the Early Post-Transplantation Period: Results from Two Cohort Studies

Abstract: Donor IL-18 rs5744247 polymorphism may influence on tacrolimus elimination. Original submitted 16 July 2014; Revision submitted 12 November 2014.

Cited by 16 publications

References 45 publications

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

Gene Variations of Sixth Complement Component Affecting Tacrolimus Metabolism in Patients with Liver Transplantation for Hepatocellular Carcinoma

Effect of CYP3A5*1 expression on tacrolimus required dose after liver transplantation: A systematic review and meta‐analysis

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