RESUMEN
STUDY OBJECTIVE: To investigate the influence of single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP2C8, CYP2J2, and UGT2B7) and transporters (ABCC2 and ABCG2) on dose and dose-adjusted trough blood concentrations (C:D ratio), clinical outcomes, and occurrence of adverse events of tacrolimus and mycophenolate sodium in Brazilian kidney transplant recipients. DESIGN: Pharmacogenetic analysis of patients enrolled in a previously published study. PATIENTS: One hundred forty-eight adult kidney transplant recipients treated with tacrolimus, enteric-coated mycophenolate sodium, and prednisone for 90 days posttransplantation. MEASUREMENTS AND MAIN RESULTS: ABCC2 c.-24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C8*3, CYP2J2 c.-76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A5*3C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus C:D values than did carriers of the c.3972CC genotype. The CYP2C8*3 variant was also associated with slightly higher tacrolimus C:D values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A5*3C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.-76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49-18.79, p<0.05). CONCLUSION: The ABCC2 c.3972C >T polymorphism affected tacrolimus C:D in Brazilian kidney transplant recipients. Further, CYP2C8*3 and CYP2J2 c.-76G>T SNPs influenced the renal function of these patients and the occurrence of adverse events during treatment with tacrolimus and mycophenolate sodium.
Asunto(s)
Citocromo P-450 CYP2C8/genética , Sistema Enzimático del Citocromo P-450/genética , Rechazo de Injerto/genética , Trasplante de Riñón , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Ácido Micofenólico/uso terapéutico , Tacrolimus/uso terapéutico , Adulto , Brasil/epidemiología , Citocromo P-450 CYP2J2 , Femenino , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/sangre , Inmunosupresores/uso terapéutico , Trasplante de Riñón/efectos adversos , Masculino , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Ácido Micofenólico/sangre , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Tacrolimus/sangre , Resultado del TratamientoRESUMEN
STUDY OBJECTIVE: To investigate the influence of single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP2C8, CYP2J2, and UGT2B7) and transporters (ABCC2 and ABCG2) on dose and dose-adjusted trough blood concentrations (C:D ratio), clinical outcomes, and occurrence of adverse events of tacrolimus and mycophenolate sodium in Brazilian kidney transplant recipients. DESIGN: Pharmacogenetic analysis of patients enrolled in a previously published study. PATIENTS: One hundred forty-eight adult kidney transplant recipients treated with tacrolimus, enteric-coated mycophenolate sodium, and prednisone for 90 days posttransplantation.MEASUREMENTS AND MAIN RESULTS:ABCC2 c.-24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C8*3, CYP2J2 c.-76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A5*3C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus C:D values than did carriers of the c.3972CC genotype. The CYP2C8*3 variant was also associated with slightly higher tacrolimus C:D values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A5*3C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.-76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49-18.79, p<0.05)...
