Influence of ABCC2, CYP2C8, and CYP2J2 Polymorphisms on Tacrolimus and Mycophenolate Sodium-Based Treatment in Brazilian Kidney Transplant Recipients

Autor(es)

Genvigir, Fabiana D. V. ; Nishikawa, Alvaro M. ; Felipe, Claudia R. ; Tedesco-Silva, Jr., Helio ; Oliveira, Nagilla ; Salazar, Antony B. C. ; Medina-Pestana, Jose O. ; Doi, Sonia Q. ; Hirata, Mario H. ; Hirata, Rosario D. C.

• Tipo de documento: Artigo Científico
• Fonte: PHARMACOTHERAPY; v. 37, n. 5, p. 535-545, MAY 2017.
• Citações Web of Science: 6

Resumo

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. (AU)

• Processo FAPESP: 11/10039-6 - Estudo da expressão e polimorfismos de genes alvo de inibidores de calcineurina em receptores de transplante renal
• Beneficiário: Rosario Dominguez Crespo Hirata
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/13118-8 - Fatores farmacogenômicos e epigenômicos relacionados com a resposta a imunossupressores em receptores de transplante renal
• Beneficiário: Rosario Dominguez Crespo Hirata
• Modalidade de apoio: Auxílio à Pesquisa - Regular