The POR rs1057868–rs2868177 GC-GT diplotype is associated with high tacrolimus concentrations in early post-renal transplant recipients

Abstract

Aim: Cytochrome P450 oxidoreductase (POR) is the only flavoprotein that donates electrons to all microsomal P450 enzymes (CYP), and several POR SNPs have been shown to be important contributors to altered CYP activity or CYP-mediated drug metabolism. In this study we examined the association between 6 POR SNPs and tacrolimus concentrations in Chinese renal transplant recipients. Methods: A total of 154 renal transplant recipients were enrolled. Genotyping of CYP3A5*3 and 6 POR SNPs was performed. All patients received a triple immunosuppressive regimen comprising tacrolimus, mycophenolate mofetil and prednisone. Dose-adjusted tacrolimus trough concentrations were obtained on d 7 (C 0D7 /D) after transplantation when steady-state concentration of tacrolimus was achieved (dosage had been unchanged for more than 3 d).Results: Tacrolimus C 0D7 /D in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype carriers was 1.62-and 2.72-fold higher than those in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype non-carriers and CYP3A5*1 carriers (220.17±48.09 vs 135.69±6.86 and 80.84±5.27 ng/mL/mg/kg, respectively, P<0.0001). Of CYP3A5*3/*3/ POR rs1057868-rs2868177GC-GT diplotype carriers, 85.71% exceeded the upper limit of the target range (8 ng/mL), which was also significantly higher compared with the latter two groups (14.29% and 0.00%, respectively, P<0.0001). The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype explained 31.7% and 5.7%, respectively, of the inter-individual variability of tacrolimus C 0D7 /D, whereas the POR rs1057868-rs2868177 GC-GT diplotype could explain 10.9% of the inter-individual variability of tacrolimus C 0D7 /D in CYP3A5 non-expressers. Conclusion: The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype accounted for the inter-individual variation of tacrolimus C 0D7 /D. Genotyping of POR rs1057868-rs2868177 diplotypes would help to differentiate initial tacrolimus dose requirements and to achieve early target C 0 ranges in Chinese renal transplant recipients.

Whole exome sequencing for the identification of CYP3A7 variants associated with tacrolimus concentrations in kidney transplant patients

“…Nevertheless, efforts are being made to discover the genetic determinants of tacrolimus PK because CYP3A5*3 is believed to account for 40‒50% of variations in tacrolimus dosage requirements 8 , and the correct dosage is still undetermined for a large proportion of patients. Recently, several other variants in CYP3A4 9 , ABCB1 10 , POR 11 , NR1I2 12 , and SUMO4 13 genes have been found to affect tacrolimus PK. However, these genetic variants do not explain the substantial variability observed for tacrolimus PK.…”

Effects of CYP3A4*22 and POR*28 variations on the pharmacokinetics of tacrolimus in renal transplant recipients: a meta-analysis of 18 observational studies

“…In addition, four studies [ 22 , 24 , 27 , 28 ] did not provide sufficient details regarding eligibility criteria, while five studies [ 23 , 25 , 33 – 35 ] did not make any reference to the exclusion criteria. Three studies did not report the results of H-W equilibrium [ 25 , 30 , 33 ], and the other three studies [ 22 , 23 , 26 ] involved insufficient demographic data without weight or percent of male. Furthermore, no publication bias was observed by the Egger’s tests except the subgroup analysis of POR*1/*1 versus POR*28 carriers in Caucasian recipients at 6 months post-transplantations ( P = 0.037).…”

Pharmacogenomics of Old and New Immunosuppressive Drugs for Precision Medicine in Kidney Transplantation

“…SNPs influencing tacrolimus C0/dose were also identified, such as IL-3 rs181781 and CTLA4 (Cytotoxic T-Lymphocyte Antigen 4) rs4553808 [ 40 ]. Indeed, patients with these polymorphisms required a lower tacrolimus C0/dose ratio, while patients with POR (Cytochrome P450 Oxidoreductase) rs1057868-rs2868177 GC-GT showed a higher tacrolimus blood concentration [ 41 ] compared with patients without these recognized polymorphisms.…”