Sombogaard Ferdi, van Schaik Ron H N, Mathot Ron A, Budde Klemens, van der Werf Marloes, Vulto Arnold G, Weimar Willem, Glander Petra, Essioux Laurent, van Gelder Teun
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands.
Pharmacogenet Genomics. 2009 Aug;19(8):626-34. doi: 10.1097/FPC.0b013e32832f5f1b.
The active metabolite of mycophenolate mofetil (MMF), mycophenolic acid, inhibits the activity of the target enzyme inosine monophosphate dehydrogenase (IMPDH). The aim of this study was to correlate eight different single nucleotide polymorphisms of the IMPDH type II gene to the activity of the IMPDH enzyme to explain between-patient differences in IMPDH activity.
In a prospective study, we measured IMPDH activity, mycophenolic acid plasma concentrations, and eight polymorphisms of IMPDH type II in de novo kidney transplant recipients, 6 days posttransplantation while on MMF treatment. Polymorphisms in the IMPDH type II gene were only observed for the IMPDH type II 3757T > C (rs11706052) single nucleotide polymorphism. Ten of 101 patients (10%) were heterozygous and two of 101 patients (2%) homozygous for IMPDH type II 3757T > C. The allele frequency was 6.9%. The IMPDH activity over 12 h (AUC(act)) was 49% higher for patients with an IMPDH type II 3757C variant [n = 12 vs. n = 68; 336 (95% confidence interval: 216-521) vs. 227 (95% confidence interval: 198-260) hmicromol/s/mol adenosine monophosphate; P = 0.04]. The IMPDH activity measured before transplantation (Act(pre-Tx)) was not significantly different between IMPDH type II 3757TT wild-type and variant carrier patients (P = 0.99).
We report that the IMPDH type II 3757T > C polymorphism is associated with an increased IMPDH activity in MMF-treated renal transplant patients. This polymorphism explains 8.0% of the interpatient variability in IMPDH activity.
霉酚酸酯（MMF）的活性代谢产物霉酚酸可抑制靶酶肌苷单磷酸脱氢酶（IMPDH）的活性。本研究旨在将IMPDH II型基因的8种不同单核苷酸多态性与IMPDH酶的活性相关联，以解释患者间IMPDH活性的差异。
在一项前瞻性研究中，我们在接受MMF治疗的初次肾移植受者移植后6天测量了IMPDH活性、霉酚酸血浆浓度以及IMPDH II型的8种多态性。仅在IMPDH II型3757T>C（rs11706052）单核苷酸多态性中观察到IMPDH II型基因的多态性。101例患者中有10例（10%）为IMPDH II型3757T>C杂合子，2例（2%）为纯合子。等位基因频率为6.9%。携带IMPDH II型3757C变异的患者12小时内的IMPDH活性（AUC(act)）比未携带变异的患者高49%[n = 12 vs. n = 68；336（95%置信区间：216 - 521）vs. 227（95%置信区间：198 - 260）h微摩尔/秒/摩尔腺苷单磷酸；P = 0.04]。在移植前测量的IMPDH活性（Act(pre - Tx)）在IMPDH II型3757TT野生型和变异携带者患者之间无显著差异（P = 0.99）。
我们报告在接受MMF治疗的肾移植患者中，IMPDH II型3757T>C多态性与IMPDH活性增加相关。这种多态性解释了患者间IMPDH活性变异的8.0%。
