Dataset Information

Multigene predictors of tacrolimus exposure in kidney transplant recipients.

ABSTRACT:

Aim

Determine the effect of the genetic variants beyond CYP3A5*3 on tacrolimus disposition.

Patients & methods

We studied genetic correlates of tacrolimus trough concentrations with POR*28, CYP3A4*22 and ABCC2 haplotypes in a large, ethnically diverse kidney transplant cohort (n = 2008).

Results

Subjects carrying one or more CYP3A5*1 alleles had lower tacrolimus trough concentrations (p = 9.2 × 10(-75)). The presence of one or two POR*28 alleles was associated with a 4.63% reduction in tacrolimus trough concentrations after adjusting for CYP3A5*1 and clinical factors (p = 0.037). In subset analyses, POR*28 was significant only in CYP3A5*3/*3 carriers (p = 0.03). The CYP3A4*22 variant and the ABBC2 haplotypes were not associated.

Conclusion

This study confirmed that CYP3A5*1 was associated with lower tacrolimus trough concentrations. POR*28 was associated with decreased tacrolimus trough concentrations although the effect was small possibly through enhanced CYP3A4 enzyme activity. CYP3A4*22 and ABCC2 haplotypes did not influence tacrolimus trough concentrations. Original submitted 19 December 2014; Revision submitted 2 April 2015.

SUBMITTER: Pulk RA

PROVIDER: S-EPMC4527535 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Tacrolimus is a calcineurin inhibitor used as an immunosuppressant drug in solid organ transplantation, and is mainly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. Studies have shown an association between the CYP3A5 genotype and tacrolimus dose-adjusted trough concentrations. Variants in the genes PPARA, POR and CYP3A4 have recently been shown to influence tacrolimus metabolism. Furthermore, pharmacokinetic interaction between corticosteroid treatment and tacrolimus has been shown. In the present study, we investigated a potential association between CYP3A5*3, PPARA c.209-1003G>A, POR*28 and CYP3A4*22 and dose-adjusted tacrolimus trough concentrations in a primarily corticosteroid-free (>85%) population of Danish pediatric and adult kidney transplant recipients.Seventy-two patients receiving treatment with oral tacrolimus were genotyped using real-time polymerase chain reaction and Primer-Probe Detection. Tacrolimus trough concentrations, corresponding doses and covariates were retrospectively collected from the patients' medical charts.It was confirmed that CYP3A5*1 wild-type carriers had lower median dose-adjusted tacrolimus trough concentrations compared with noncarriers. Adults had 56 and 77% lower trough concentrations at 6 weeks (p = 0.0003) and 1 year, respectively (p < 0.0017), and, similarly, children had 65 and 39% lower median concentrations, with p values of 0.006 and 0.011, respectively. No association was found for PPARA c.209-1003G>A, POR*28, or CYP3A4*22. An association between the PPARA c.209-1003G>A genotype and an increased number of infections with cytomegalovirus (CMV) within the first year was identified (p < 0.05). Only 29% of trough concentrations measured between 2 and 12 weeks post-transplantation were on target.This study shows that the known association of the CYP3A5 genotype with tacrolimus dose-adjusted trough concentrations has the same impact in a corticosteroid-sparse population. The association between PPARA variance and infections with CMV will need further investigation.