title: Association between interleukin-18 promoter variants and tacrolimus pharmacokinetics in Chinese renal transplant patients.
abstract: OBJECTIVE
  Interleukin 18 (IL-18) is a potent proinflammatory cytokine thought to down-regulate cytochrome P450 (CYP) enzyme activities. This study aimed to assess the potential influence of two functional single nucleotide polymorphisms (SNPs) in the IL-18 promoter region on the tacrolimus pharmacokinetics in Chinese renal transplant patients.
  
  
  METHODS
  We enrolled 96 renal allograft recipients receiving tacrolimus-based immunosuppressive regiments. Two functional SNPs in the IL-18 gene promoter region at the positions -137G/C (rs187283) and -607A/C (rs1946518) and one SNP (rs776746) of CYP3A5 were genotyped using a Mass ARRAY platform. Tacrolimus daily doses (mg/day) and trough tacrolimus concentration (ng/ml) were continuously recorded for 1 month after transplantation.
  
  
  RESULTS
  The tacrolimus C/D ratio was significantly associated with the IL-18 rs1946518 gene polymorphism in the first month after transplantation (P = 0.0225). We studied the influence of its polymorphism on tacrolimus C/D ratios in subjects with different CYP3A5 genotype backgrounds, and among patients with CYP3A5 expressers, the difference among the three genotypes was even more striking (P < 0.001). We did not find significant differences in tacrolimus C/D ratios between the IL-18 rs187238 genotypes, either nominally or according to the CYP3A5 genotype. In a simple linear regression model, age, hemoglobin (Hb), CYP3A5 gene polymorphisms, and IL-18 A-607C gene polymorphisms were associated with log-transformed tacrolimus C/D ratios (P < 0.05). In the final multiple linear regression model, CYP3A5 polymorphisms were the most important variant, accounting for 19.5 % of total variation involved in tacrolimus pharmacokinetics.
  
  
  CONCLUSIONS
  Our findings suggest that a combined analysis of CYP3A5 and IL-18 promoter polymorphisms may help clinicians develop individualized tacrolimus treatment, which is based on determining CYP3A5 genotype.
authors.affiliation: Department of Urology Surgery, Shandong Qianfoshan Hospital, School of Medicine, Taishan Medical College, Shandong, China.
authors.forename: Jiazhen
authors.initials: J
authors.lastname: Xing
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Zhang
authors.forename: Junwei
authors.initials: J
authors.lastname: Fan
authors.forename: Bin
authors.initials: B
authors.lastname: Shen
authors.forename: Tongyi
authors.initials: T
authors.lastname: Men
authors.forename: Jianning
authors.initials: J
authors.lastname: Wang
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D020382:Interleukin-18 / Q000235:genetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; D020382:Interleukin-18; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus