Abstract
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.