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

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Chinese Medical Journal 2017年第14期130卷 1670-1676页

作者： Jian-Hua Liao Chang-Can Li Shao-Han Wu Jun-Wei Fan Hai-Tao Gu Zhao-Wen Wang Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200080 China

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 tacrolilnus 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 l,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 l,111.06 at week 2,77.49 at week 3,and 85.60 at week 4） and C6 rs 10052999 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 metabolis

关键词： C6 cytochrome p450 3a5 Hepatocellular Carcinoma Liver Transplantation Single Nucleotide polymorphism Tacrolimus Metabolism

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