Influence of the CYP3A4/5 genetic score and ABCB1 polymorphisms on tacrolimus exposure and renal function in Brazilian kidney transplant patients

Influence of the CYP3A4/5 genetic score and ABCB1 polymorphisms on tacrolimus exposure and renal function in Brazilian kidney transplant patients

Author Genvigir, Fabiana D. V. Google Scholar
Salgado, Patricia C. Google Scholar
Felipe, Claudia Rosso Autor UNIFESP Google Scholar
Luo, Elena Y. F. Google Scholar
Alves, Camila Google Scholar
Cerda, Alvaro Google Scholar
Tedesco-Silva Junior, Hélio Autor UNIFESP Google Scholar
Pestana, Jose Osmar Medina Autor UNIFESP Google Scholar
Oliveira, Nagilla Ione de Autor UNIFESP Google Scholar
Rodrigues, Alice C. Google Scholar
Doi, Sonia Q. Google Scholar
Hirata, Mario H. Google Scholar
Hirata, Rosario D. C. Google Scholar
Abstract BackgroundPolymorphisms in genes encoding transport proteins and metabolizing enzymes involved in tacrolimus (TAC) disposition may be important sources of individual variability during treatment.ObjectiveThe aim of this study was to investigate the effect of combined CYP3A4 and CYP3A5 variants, using a CYP3A4/5 genetic score, and ABCB1 polymorphisms on therapeutic TAC monitoring and their relationship with clinical outcomes.Material and methodsBrazilian kidney transplant recipients (n=151), who received TAC over 3 months after transplantation, were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T) and rs776746 (g.6986A>G), ABCB1 rs1128503 (c.1236C>T), rs1045642 (c.3435C>T), and rs2032582 (c.2677G>T/A) polymorphisms.ResultsFrequencies of CYP3A4 g.20230A, CYP3A5 g.31611C, and g.6986A were 0.37, 0.26, and 0.28, respectively. These alleles were associated with TAC rapid metabolization and were used for CYP3A4/5 genetic score construction. A higher CYP3A4/5 genetic score was associated with higher TAC dose and lower concentrations for dose administered (Co/D, P<0.05). Ninety days after transplantation, the presence of two or more rapid metabolization alleles contributed toward 27.7% of Co/D variability and was associated with a lower estimated glomerular filtration rate values (P<0.05). For ABCB1, the frequencies of c.1236T, c.3435T, and c.2677T/A alleles were 0.42, 0.42, and 0.33/0.04. At 30 days after transplantation, patients carrying ABCB1 c.1236TT+c.3435TT+(c.2677TT+TA) genotypes had higher TAC Co/D than those with common or heterozygous genotypes (P<0.05).ConclusionThe results show the impact of the CYP3A4/5 genetic score on TAC exposure and renal function in Brazilian patients. Furthermore, ABCB1 polymorphisms, in a combined analysis, influenced TAC Co/D at 30 days after transplantation.
Keywords ABCB1
CYP3A4
CYP3A5
genetic score
polymorphism
renal transplantation
tacrolimus
xmlui.dri2xhtml.METS-1.0.item-coverage Philadelphia
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Grant number FAPESP: 2011/10039-6
Date 2016
Published in Pharmacogenetics And Genomics. Philadelphia, v. 26, n. 10, p. 462-472, 2016.
ISSN 1744-6872 (Sherpa/Romeo, impact factor)
Publisher Lippincott Williams & Wilkins
Extent 462-472
Origin http://dx.doi.org/10.1097/FPC.0000000000000237
Access rights Closed access
Type Article
Web of Science ID WOS:000384519700003
URI https://repositorio.unifesp.br/handle/11600/57026

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