Polymorphisms in IMPDH2, UGT2B7, and CES2 genes influence the risk of graft rejection in kidney transplant recipients taking mycophenolate mofetil

https://doi.org/10.1016/j.mrgentox.2018.06.008Get rights and content

Highlights

  • The SNP rs11706052 (IMPDH2) showed a 4.2-fold protection against graft rejection.

  • The SNP rs7438135 (UGT2B7) showed a 2.4-fold protection, against graft rejection.

  • The SNP rs2241409 (CES2) was associated with a 7.2-fold increased risk of rejection.

  • SNPs in IMPDH2, UGT2B7 and CES2 genes are potential prognostic markers for rejection.

Abstract

The immunosuppressant mycophenolic acid (MPA), derived from the prodrug mycophenolate mofetil (MMF), is a drug used widely by kidney transplant recipients. This drug selectively inhibits inosine monophosphate dehydrogenase that controls the proliferation of lymphocytes, aiding in the prevention of rejection of the transplanted organ. Polymorphisms in key genes involved in MMF metabolism may alter the function of the enzymes encoded by them and contribute to interindividual variability in the response to the drug and its efficacy. The aim of this study was to investigate the association of nine polymorphic variants of eight genes involved in MMF pharmacokinetics, with rejection and adverse effects exhibited by kidney transplant recipients who use this drug. Our sample comprised 145 kidney transplant recipients undergoing post-transplant treatment whose immunosuppressive therapy consisted of MMF and corticosteroid combined or not with a calcineurin inhibitor or mTOR inhibitor. The average age of the patients was 46.9 ± 12.5 years, and they underwent transplantation 7 ± 5.71 years ago. The combination of the T/C and C/C genotypes of the polymorphism rs11706052 (IMPDH2) was associated with a 4.2-fold protection, and the combination of the genotypes A/G and G/G of the polymorphism rs7438135 (UGT2B7) showed a 2.4-fold protection, against rejection. The association of T/C and C/C genotypes in the SNP rs11706052 (IMPDH2) with the occurrence of rejection episodes considering only patients who received immunosuppressive drug MMF associated with cyclosporine or tacrolimus and corticoids, demonstrated association with a protection against rejection 15.6-fold. The T/T genotype of the polymorphism rs2241409 (CES2) was associated with a 7.2-fold increased risk of rejection. Therefore, these polymorphisms that showed a strong association with rejection episodes should be considered in future studies on new prognostic markers for rejection in patients treated with MMF.

Introduction

Mycophenolate mofetil (MMF) is a drug widely used as an immunomodulator by transplant patients [1,2] and patients with autoimmune diseases [3]. MMF therapy is commonly combined with calcineurin inhibitors and corticoids in kidney transplant recipients, they act at different stages of the lymphocyte proliferation pathway, inhibiting lymphocyte proliferation and preventing organ rejection [4].

MMF is a prodrug, which is hydrolyzed to mycophenolic acid (MPA) (Fig. 1) after oral administration. Though this activation the drug occurs mainly in the liver catalyzed by the carboxylesterase enzymes, CES1 and CES2, it may also be present in the intestine and blood through the action of CES2 and acetylcholinesterase, respectively [5,6]. Hence, polymorphisms in genes responsible for MMF activation may contribute to interindividual variations and affect the efficacy of this drug (Fig. 2).

The immunosuppressive activity of MPA occurs through inhibition of inosine 5′-monophosphate dehydrogenase (IMPDH) [6], which leads to reduction in guanine nucleotide synthesis that is essential for DNA synthesis. Selective inhibition of T and B lymphocyte proliferation occurs because lymphocytes, unlike other cell types, are exclusively dependent on the pathway catalyzed by IMPDH for guanine nucleotide synthesis [7].

In addition to causing depletion of guanine nucleotides, MPA also induces apoptosis in activated T lymphocytes, inhibits the formation of antibodies and the expression of glycoproteins and adhesion molecules responsible for the recruitment of monocytes and lymphocytes to sites of inflammation, which occurs during graft rejection [1,8,9].

IMPDH has two isoforms, IMPDH1 and IMPDH2, which are located on chromosomes 7q31.3 and 3p21.2, respectively and show 84% homology [10]. IMPDH1 is expressed in all tissues to maintain the basal level of guanine nucleotides, while IMPDH2 is expressed in activated lymphocytes thus increasing their proliferation [1]. Variations in the activity of these proteins are observed among patients and can be explained by the presence of genetic polymorphisms. However, knowledge of the consequences of polymorphisms and their association with the response to MPA treatment is still scarce [2].

The inactivation of MPA is catalyzed by uridine 5′-diphospho-glucuronosyltransferases (UGTs). The UGT2B7 enzyme transforms MPA into MPA acyl glucuronide (AcMPAG) and the enzyme UGT1A9 transforms MPA into MPA glucuronide (MPAG). These two metabolites are excreted in the urine and bile. Biliary excretion is performed by multidrug resistance protein 2 (MRP2/ABCC2) and organic anion-transporting polypeptides (SLCO1B1) present on the surface of hepatocytes; a part of the excreted MPAG undergoes intestinal bacterial deconjugation, returns to its active form, and contributes to the enterohepatic recirculation of MPA [8,11,12].

Polymorphisms in genes related to MMF activation (CES1 and CES2), to the mechanism of action (IMPDH1 and IMPDH2), to drug transporters (ABCC2 and SLCO1B1), and MPA inactivation (UGT1A9 and UGT2B7), may affect drug availability and cause interindividual variations in the efficacy of treatment with MPA. In this study nine single nucleotide polymorphisms (SNPs) were selected in genes that are involved in the pharmacokinetics/pharmacodynamics of MMF to assess whether they contribute to the incidence of rejection in kidney transplant recipients.

Section snippets

Population studied

A total of 145 kidney transplant recipients undergoing post-transplant treatment at the Kidney Institute of Londrina (Londrina, PR, Brazil) which immunosuppressive therapy consisted of MMF and corticosteroid combined or not with a calcineurin inhibitor or mTOR inhibitor were selected. These patients were classified into two groups, those who had graft rejection episodes (N = 49) and those with none (N = 96). Graft rejection episodes were confirmed by histopathological examination of the graft

Results

Table 2 shows the demographic data and clinical characteristics of patients with (33.8%) and without (66.2%) rejection. Differences were observed between patients with and without rejection when compared three variables, time after transplantation, alcohol consumption and ancestry (Student’s t test, p < 0.050).

Of the nine SNPs evaluated, rs11706052 (IMPDH2) and rs7438135 (UGT2B7) showed a significant association with protection against rejection episodes and rs2241409 (CES2) was associated with

Discussion

In the present study we found that renal transplant patients who used any amount of alcohol had an increase of 3.68-fold (p = 0.012) of rejection episodes (univariate logistic regression). According to a review performed by Parker et al. [20] alcohol consumption after transplantation is associated with poor medication compliance and this may increase risk of graft loss; others authors showed that the consume of alcohol may induce complications of hypertension [21] that contributes with kidney

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgments

The authors thank the Kidney Institute of Londrina for support and partnership and the transplant patients that participated of the study. The authors are grateful for the assistance given by Ms. Sandra Lopes and Ms. Madalena Pikina (Clinilab, Londrina, Brazil). This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) [grant number 470398/2014-0] and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/PROAP). H.L. Cilião received

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