Cilião Heloísa Lizotti, Camargo-Godoy Rossana Batista Oliveira, Souza Marilesia Ferreira de, Zanuto Amanda, Delfino Vinicius Daher Alvares, Cólus Ilce Mara de Syllos
Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil.
Center of Health Sciences, State University of Londrina, Londrina, Paraná, Brazil.
Mutat Res Genet Toxicol Environ Mutagen. 2018 Dec;836(Pt B):97-102. doi: 10.1016/j.mrgentox.2018.06.008. Epub 2018 Jun 1.
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.
免疫抑制剂霉酚酸（MPA）由前体药物霉酚酸酯（MMF）衍生而来，是肾移植受者广泛使用的一种药物。该药物选择性抑制肌苷单磷酸脱氢酶，从而控制淋巴细胞的增殖，有助于预防移植器官的排斥反应。MMF代谢相关关键基因的多态性可能会改变其编码酶的功能，并导致个体对该药物反应及其疗效的差异。本研究的目的是调查参与MMF药代动力学的8个基因的9个多态性变体与使用该药物的肾移植受者出现的排斥反应和不良反应之间的关联。我们的样本包括145名接受移植后治疗的肾移植受者，他们的免疫抑制治疗方案包括MMF与皮质类固醇联合使用，或不与钙调神经磷酸酶抑制剂或mTOR抑制剂联合使用。患者的平均年龄为4岁。6.9±12.5岁，他们在7±5.71年前接受了移植手术。rs11706052（IMPDH2）多态性的T/C和C/C基因型组合与4.2倍的保护作用相关，rs7438135（UGT2B7）多态性的A/G和G/G基因型组合显示出2.4倍的保护作用，可预防排斥反应。仅考虑接受与环孢素或他克莫司及皮质类固醇联合使用的免疫抑制药物MMF的患者，SNP rs11706052（IMPDH2）中T/C和C/C基因型与排斥反应发作的关联表明其与15.6倍的排斥保护作用相关。rs2241409（CES2）多态性的T/T基因型与排斥风险增加7.2倍相关。因此，在未来关于MMF治疗患者排斥反应新预后标志物的研究中，应考虑这些与排斥反应发作密切相关的多态性。
