Department of Pharmacology, Pomeranian Medical University, Powstańców Wlkp. 72, PL 70-111 Szczecin, Poland.
Pharmacol Rep. 2011;63(3):826-33. doi: 10.1016/s1734-1140(11)70595-3.
New onset posttransplant diabetes mellitus (PTDM) has a high incidence after kidney transplantation in patients medicated with tacrolimus. PTDM can adversely affect patient and graft survival. The pathophysiology of PTDM closely mimics type 2 diabetes mellitus (T2DM). One of the possible genetic factors predisposing individuals to PTDM might be a polymorphism in the transcription factor 7-like 2 gene (TCF7L2). This polymorphism has previously been associated with increased risk of T2DM in the general population. Therefore, the present study aimed to evaluate TCF7L2 polymorphisms in PTDM in kidney transplant patients medicated with tacrolimus. Non-diabetic kidney transplant patients medicated with tacrolimus (n = 234) were genotyped for the presence of TCF7L2 gene variants (rs12255372 and rs7903146) using TaqMan probes. Of the 234 patients, 66 patients had developed PTDM and 168 had not. Frequencies of the studied single nucleotide polymorphisms (SNPs) did not differ significantly between the study groups. Moreover, haplotype analyses failed to detect any associations between TCF7L2 haplotypes and PTDM. However, in late-onset PTDM (developed later that 2 weeks from transplantation), frequencies of the rs7903146 TT genotype and T minor allele were significantly increased compared to non-PTDM controls (17.9% vs. 5.9%, p = 0.017, OR: 4.13, 95% CI: 1.19-14.33 for TT genotype, 39.3% vs. 25.9%, p = 0.038 for T allele). If the application of TCF7L2 rs7903146 SNPs as a marker for PTDM is confirmed by further independent studies, replacing tacrolimus with other immunosuppressants could be warranted in patients at high risk of PTDM, as diagnosed by TCF7L2 genotyping.
新诊断的移植后糖尿病（PTDM）在接受他克莫司治疗的肾移植患者中发病率很高。PTDM 会对患者和移植物的存活产生不利影响。PTDM 的病理生理学与 2 型糖尿病（T2DM）非常相似。导致个体易患 PTDM 的可能遗传因素之一可能是转录因子 7 样 2 基因（TCF7L2）的多态性。该多态性先前与一般人群中 T2DM 的风险增加有关。因此，本研究旨在评估接受他克莫司治疗的肾移植患者中 TCF7L2 多态性与 PTDM 的关系。使用 TaqMan 探针对 234 例接受他克莫司治疗的非糖尿病肾移植患者进行 TCF7L2 基因变异（rs12255372 和 rs7903146）的基因型分析。在 234 例患者中，66 例发生 PTDM，168 例未发生。研究组之间研究的单核苷酸多态性（SNP）的频率无显著差异。此外，TCF7L2 单倍型分析未能发现 TCF7L2 单倍型与 PTDM 之间存在任何关联。然而，在迟发性 PTDM（发生在移植后 2 周内）中，rs7903146 TT 基因型和 T 等位基因的频率与非 PTDM 对照组相比显著增加（17.9%对 5.9%，p = 0.017，OR：4.13，95%CI：1.19-14.33 为 TT 基因型，39.3%对 25.9%，p = 0.038 为 T 等位基因）。如果进一步的独立研究证实 TCF7L2 rs7903146 SNP 作为 PTDM 的标志物，那么在 TCF7L2 基因分型诊断为 PTDM 高风险的患者中，可能需要用其他免疫抑制剂替代他克莫司。
