Impact of PPARA and POR polymorphisms on tacrolimus pharmacokinetics and new-onset diabetes in kidney transplant recipients

Abstract

Recent efforts have been made to identify genetic markers of CYP3A4 enzymatic activity within genes encoding for regulatory elements. The aim of the current study was to investigate the impact of polymorphism of PPARA and POR genes on tacrolimus (TAC) dose-adjusted trough concentration and risk of new-onset diabetes after transplantation (NODAT). A total of 241 White kidney transplant patients were genotyped for three functional single nucleotide polymorphisms: rs1057868 (*28) in POR, rs4253728:G>A, and rs4823613:A>G in PPARA. No significant genotype-dependent differences in TAC dose-adjusted trough concentration were observed for either POR or PPARA variants. No significant differences in the incidence of NODAT were observed between patients stratified by PPARA and POR genotypes. The frequency of NODAT among PPARA rs4253728 AA homozygotes (42%) was higher compared with heterozygotes (22%) and GG homozygotes (19%), but the difference was not significant. Testing TAC-medicated renal transplant recipients for POR and PPARA variants seems to have limited clinical application.

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

“…By contrast, POR*28 has been reported to be associated with lower tacrolimus concentrations in CYP3A5 expressers [24,25] or nonexpressers [26,27] , suggesting that POR*28 variant may enhance CYP3A4 or CYP3A5 enzyme activity. Moreover, no significant association between POR*28 and tacrolimus concentration was found in the present study, which is in line with a study also conducted in Chinese early post-renal transplant recipients [28] and two studies conducted in Caucasian early or stable renal transplant recipients [15,29] . The reason for the discrepancy among these studies is not clear, but several possibilities may be involved.…”

“…Intronic SNPs-rs2302429, rs2286823 (IVS11±20G>A) and rs41301394 (831-35C>T) have been significantly associated with the altered CYP1A2, CYP2C19, or CYP3A4 activities [13,14] . Rs2868177 has been found to be associated with the cardiotoxicity induced by daunorubicin, which is also a substrate of CYP3A [15] . Moreover, rs2868177 and other two SNPs (rs17148944 and rs17685) have been brought into warfarin pharmacogenetic research and reported to be correlated with warfarin maintenance dose [16] .…”

Genetic factors in pathogenesis of diabetes mellitus after kidney transplantation

“…Elens et al observed an association between a coding POR variant (rs1057868) and 2 single-nucleotide substitutions in PPARα (rs4823613 and rs4253728) and increased risk for PTDM 53. However, this result was not confirmed by Kurzawski et al in a subsequent study 54. Recently, Gervasini et al focused on cytochrome P450 enzymes in 164 patients and showed that a valine-to-methionine amino acid change in residue 433 of the CYP4F2 gene (rs2108622) is an independent risk factor of PTDM 55.…”

Role of pharmacogenomics in dialysis and transplantation

“…The gene PPARA encodes the perixosome proliferator-activated receptor alpha (PPAR-α), and variants rs4253728, G>A and rs4823613, A>G affect CYP3A activity. Initial studies of PPARA and tacrolimus show conflicting results (21, 35). These newly described variants will need further validation across populations before deciding their clinical importance.…”