Association Between Interleukin-18 Promoter Variants And Tacrolimus Pharmacokinetics In Chinese Renal Transplant Patients

ObjectiveTacrolimus,a calcineurin inhibitor in T lymphocytes,is a widely used immunosuppressant in organ transplantation to prevent allograft rejection and improve patient survival.Tacrolimus is characterized by a narrow therapeutic index and a broad pharmacokinetic inter-individual variability,which makes therapeutic drug monitoring necessary to avoid underdosing or overdosing.CYP3 A enzymes,which are mainly expressed in the liver and intestine,are major tacrolimus metabolic enzymes.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,CYP3A5,and CYP3A4rs12333983 on the tacrolimus pharmacokinetics in Chinese renal transplant patients.MethodsIL-18 promoter region SNP-607C/A(rs1946518),-137G/C(rs187283),CYP3A4rs12333983,and CYP3A5 genotype frequency and allele frequency of 96 renal allograft recipients receiving tacrolimus-based immunosuppressive regiments were tested by using the pyrosequencing assays.Age,year,weight,hemoglobin(Hb),albumin,Tacrolimus daily doses(mg/d)and trough tacrolimus concentration(ng/ml)were continuously recorded for1 month after transplantation.Result1.GG genotype of CYP3A5 was observed in 46 patients,AG genotype in 42 patients,AA genotype in 8 patients,and A allele was found to be the minor allele(30%).We grouped patients with AG and AA genotype together,named CYP3A5 expressers.The patients with the GG genotype were named nonexpressers.For CYP3A4 rs12333983,48 patients were homozygous for the CYP3A4 wild type(rs12333983TT),32 were heterozygous(rs12333983AT),and 6 were homozygous for the A variant(rs12333983AA),resulting in a minor-allele(A)frequency of 32.2%.CC genotype of IL-18-137C/A was observed in 24 patients,CA genotype in 46 patients,AA genotype in 26 patients.GG genotype of IL-18 G/C was observed in 74 patients,GC genotype in 21 patients,CC genotype in 1 patients,and C allele was found to be the minor allele(12%),we grouped patients with CC and CG genotype together.2.Tacrolimus C/D ratios of the CYP3A5 rs776746 genotype GG carriers at 4 weeks were88.4?91.3?103.9 and 111.5 respectively,while C/D ratios of the AG+AA carriers were69.6?74.2?86.3 and 88.0,respectively.The differences between the two groups were significant(P = 0.033,0.031,0.047,and 0.001,respectively).The median of tacrolimus C/D ratios of CYP3A4 rs12333983 allele A carriers at weeks 1,2,3,and 4 were 62.6,65.7,78.8 and 93.9 respectively,while C/D ratios of non-carriers were 70.3?74.9?85.0 and101.4,respectively,which indicated a significant difference in week1,3,and 4.(P=0.036?0.058?0.047 and 0.045,respectively).Tacrolimus C/D ratios of the IL-18 rs1946518 genotype CC carriers at 4 weeks were87.3,89.3,104.0,and 109.5,respectively;the CA carriers were 79.3,82.8,93.9,and 98.0,respectively;and the AA carriers were 64.8,66.5,84.8,and 90.1,respectively.The differences among the three groups were significant at week 3(P = 0.039)and marginally significant at weeks 1 and 4(P = 0.076 and 0.058,respectively).Because the CC group was so small,we combined the GC and CC group.Tacrolimus C/D ratios of the IL-18 rs187238 genotype CC+AG carriers at 4 weeks were 78.1,79.3,96.7,and 98.2,respectively,while C/D ratios of the GG carriers were 80.4,82.6,104.5,and 110.8,respectively.However,there were no significant differences between the two groups(P = 0.368,0.312,0.197,and0.286,respectively).3.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-18rs187238 genotypes,either nominally or according to the CYP3A5 genotype.4.In a simple linear regression model,age,hemoglobin(Hb),CYP3A5 gene polymorphisms,and IL-18 A-607 C 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.ConclusionsOur 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.