title: Influence of TLR4 rs1927907 locus polymorphisms on tacrolimus pharmacokinetics in the early stage after liver transplantation.
abstract: OBJECTIVE
  The aim of this study was to assess the potential influence of single nucleotide polymorphisms (SNPs) in the TLR4 gene on tacrolimus pharmacokinetics in the early stage after liver transplantation.
  
  
  METHODS
  A total of 96 liver transplant patients receiving tacrolimus-based immunosuppressive regimens were enrolled in this study. The SNPs of CYP3A5 rs776746 and TLR4 rs1927907 were genotyped in both donors and recipients. Trough tacrolimus concentration (ng/mL) and tacrolimus daily doses (mg/day) were recorded for the first 4 weeks post-transplantation. The tacrolimus dose-adjusted trough concentrations (C/D ratio) required to achieve target concentrations were compared among patients according to allele status for CYP3A5 rs776746 and TLR4 rs1927907 during the first 4 weeks post-transplantation.
  
  
  RESULTS
  Both donor and recipient CYP3A5 rs776746 allele A and donor TLR4 rs1927907 allele A were associated with a lower C/D ratio during the early stage after transplantation. The difference was even more striking in patients with both the CYP3A5 and TLR4 genotypes. With increasing numbers of genotype AA/AG, patients were found to have increasingly lower tacrolimus C/D ratios at all time points between post-transplantation weeks 1 and 4.
  
  
  CONCLUSIONS
  Collectively, donor TLR4 rs1927907 SNPs were closely associated with tacrolimus elimination in our Chinese Han patient population. The combination of the donor TLR4 rs1927907 SNP and both donor and recipient CYP3A5 rs776746 SNP might have a greater effect on tacrolimus elimination than each SNP separately. Screening for these SNPs prior to liver transplantation might be useful for determining adequate initial daily doses of immunosuppressive agents and achieving the desired immunosuppressive effect.
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, No.100, Haining Road, Shanghai City, China.
authors.forename: Zhaowen
authors.initials: Z
authors.lastname: Wang
authors.forename: Shaohan
authors.initials: S
authors.lastname: Wu
authors.forename: Dawei
authors.initials: D
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.forename: Lin
authors.initials: L
authors.lastname: Zhong
authors.forename: Junwei
authors.initials: J
authors.lastname: Fan
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Peng
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D044466:Asian People / Q000235:genetics; D001219:Aspartate Aminotransferases / Q000097:blood; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D007166:Immunosuppressive Agents; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D016559:Tacrolimus