| BACKGROUND:Cyclosporine A(CsA)has become an alternative to calcineurin inhibitors due to its immunosuppressive properties in heart transplant(HTx)recipients.However,CsA dosing is challenging due to its considerable toxicity,narrow therapeutic windows combined with high inter-individual pharmacokinetic variability.Although genetic polymorphisms have been shown to influence pharmacokinetics of immunosuppressants,data in the context of Chinese HTx recipients are scarce till now.This is the first study to evaluate the effect of CYP3A5 genetic polymorphisms on CsA blood dose-adjusted concentrations(C/D)and other clinical outcomes,such as the classifications of endomyocardial biopsy and long-term prognosis in a pilot cohort of 90 Chinese HTx recipients.METHODS:We retrospectively enrolled a set of consecutive HTx recipients from Aug.2005 to Jul.2012 in Fuwai hospital.Associations between CYP3A5 genotypes and C/D of CsA at 1,3,6,and 12 months after hart transplant were analyzed in cohorts of 90 patients.In addition,we also evaluated the associations between CYP3A5 genotypes and the classifications of endomyocardial biopsy and long-term prognosis in the 90 Chinese HTx patients.RESULTS:The recipients with wild homozygote AA(CYP3A5*1/*1),mutant heterozygote GA(CYP3A5*1/*3),and mutant homozygote GG(CYP3A5*3/*3)were 7,34 and 49 cases,respectively.The gene mutation rate of CYP3A5*3 in this cohort of Chinese HTx recipients was 73.3%and the homozygous proportion was 54.4%.There were no significant difference between CYP3A5 genetic polymorphisms and CsA C/D at all studied time points(1 month:63.29± 11.15 vs 67.72± 17.65 vs 66.99± 13.46,P=0.784;3 months:78.45±23.16 vs 72.76±21.85 vs 70.08±23.09,p=0.674;6 months:65.89±22.42 vs 66.30± 17.46 vs 68.03±24.76,p=0.931;12 months:73.99±19.29 vs 66.28± 18.63 vs 67.50±21.01,p=0.671);as well as the classification of endomyocardial biopsy(1 month:1.14±0.38 vs 1.53 ±0.88 vs 1.45±0.85,P=0.218;3 months:1.50±0.58 vs 1.70±0.89 vs 1.89±1.00,P=0.245;6 months:1.00±0.00 vs 1.58±0.96 vs 1.90±1.17,P=0.086),mortality due to acute organ rejection(0%vs 0%vs 2%,P= 0.655)and all-cause mortality(14.3%vs 0%vs 10.2%,P=0.131).CONCLUSIONS:In Chinese HTx recipients,no significant associations were observed between CYP3A5 polymorphisms and the CsA C/D and other clinical outcomes,such as the classifications of endomyocardial biopsy and long-term mortality.BACKGROUND:Tacrolimus(Tac)has become an alternative to calcineurin inhibitors due to its immunosuppressive properties in heart transplant(HTx)recipients.However,Tac dosing is challenging due to its considerable toxicity,narrow therapeutic windows combined with high inter-individual pharmacokinetic variability.Although genetic polymorphisms have been shown to influence pharmacokinetics of immunosuppressants,data in the context of Chinese HTx recipients are scarce till now.This is the first study to evaluate the effect of CYP3A5 genetic polymorphisms on Tac blood dose-adjusted concentrations(C/D)and other clinical outcomes,such as the classifications of endomyocardial biopsy and long-term prognosis in a pilot cohort of 113 Chinese HTx recipients.METHODS:We retrospectively enrolled a set of consecutive HTx recipients from Aug.2005 to Jul.2012 in Fuwai hospital.Associations between CYP3A5 genotypes and C/D of Tac at 1,3,6,and 12 months since the beginning of immunosuppressive therapy were analyzed in cohorts of 113 patients.In addition,we also evaluated the associations between CYP3A5 genotypes and the classifications of endomyocardial biopsy and long-term prognosis in the 113 Chinese HTx patients.RESULTS:The recipients with wild homozygote AA(CYP3A5*1/*1),mutant homozygote GG(CYP3A5*3/*3),and mutant heterozygote GA(CYP3A5*1/1*3)were 5,74 and 34 cases,respectively.The gene mutation rate of CYP3A5*3 in this cohort of Chinese HTx recipients was 80.5%and the homozygous proportion was 65.5%.Tac C/D at 1 month in CYP3A5-nonexpressors(*3/*3)was higher than CYP3A5-expressors(*1/*3or*1/*1)(293.70±171.20vs116.11±42.40vs 47.34±11.40,P=0.000),so were the other studied time points(3 months:98.32±39.43 vs 292.07±141.08,P=0.003;6 months:90.00±21.31 vs 341.68±165.02,P=0.002;and 12 months:96.02±29.33 vs 339.23±162.30,P=0.018);and CYP3A5-nonexpressors may have a lower classification of endomyocardial biopsy at 1 month(1.43 ±0.73 vs 1.50±0.58,P=0.867),3 months(1.55±1.00 vs 2.00±1.73,P=0.512),and 6 months(1.36±0.84 vs 2.33±1.53,P=0.132);as well as a higher mortality due to acute organ rejection(10%vs 0%,P=0.244)and all-cause mortality(20%vs 9.7%,P= 0.580).CONCLUSIONS:In Chinese HTx recipients,CYP3A5-nonexpressors is confirmed to be associated with slower Tac metabolism.The CYP3A5 nonexpressors may have a lower risk of acute organ rejection within 6 months after transplantation.In addition,the frequency of this*3 allele is lower than that has been reported in the white population.The determinations of CYP3A5 gene-types in heart transplant recipients are helpful to guide the individualized Tac regimens. |
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