Dataset Information

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

ABSTRACT: 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.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.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).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.

SUBMITTER: Liao JH

PROVIDER: S-EPMC5520553 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Liao Jian-Hua JH Li Chang-Can CC Wu Shao-Han SH Fan Jun-Wei JW Gu Hai-Tao HT Wang Zhao-Wen ZW

Chinese medical journal 20170701 14

<h4>Background</h4>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 wa ...[more]

PMID: 28685716

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Project description:It is well known that the CYP3A5*3 polymorphism is an important marker that correlates with the tacrolimus dose requirement after organ transplantation. Recently, it has been revealed that the POR*28 polymorphism affects the pharmacokinetics of tacrolimus in renal transplant patients. In this study, we examined whether POR*28 as well as CYP3A5*3 polymorphism in Japanese recipients and donors would be another biomarker for the variation of tacrolimus blood levels in the recipients during the first month after living-donor liver transplantation. We enrolled 65 patients treated with tacrolimus, who underwent liver transplantation between July 2016 and January 2019. Genomic DNA was extracted from whole-blood samples, and genotyping was performed to examine the presence of CYP3A5*3 and POR*28 polymorphisms in the recipients and donors. The CYP3A5*3/*3 genotype (defective CYP3A5) of the recipient (standard partial regression coefficient [median C/D ratio of CYP3A5 expressor vs. CYP3A5 non-expressor, p value]: Pod 1-7, ?= -0.389 [1.76 vs. 2.73, p < 0.001]; Pod 8-14, ? = -0.345 [2.03 vs. 2.83, p < 0.001]; Pod 15-21, ?= -0.417 [1.75 vs. 2.94, p < 0.001]; Pod 22-28, ? = -0.627 [1.55 vs. 2.90, p < 0.001]) rather than donor (Pod 1-7, ? = n/a [1.88 vs. 2.76]; Pod 8-14, ? = n/a [1.99 vs. 2.93]; Pod 15-21, ? = -0.175 [1.91 vs. 2.94, p = 0.004]; Pod 22-28, ? = n/a [1.61 vs. 2.67]) significantly contributed to the increase in the concentration/dose (C/D) ratio of tacrolimus for at least one month after surgery. We found that the tacrolimus C/D ratio significantly decreased from the third week after transplantation when the recipient carried both CYP3A5*1 (functional CYP3A5) and POR*28 (n = 19 [29.2%], median C/D ratio [inter quartile range] = 1.58 [1.39-2.17]), compared with that in the recipients carrying CYP3A5*1 and POR*1/*1 (n = 8 [12.3%], median C/D ratio [inter quartile range] = 2.23 [2.05-3.06]) (p < 0.001). In conclusion, to our knowledge, this is the first report suggesting that the POR*28 polymorphism is another biomarker for the tacrolimus oral dosage after liver transplantation in patients carrying CYP3A5*1 rather than CYP3A5*3/*3.

Dataset Information

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

Publications

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

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