Choi Rihwa, Lee Mi-Na, Kim Kyunga, Baek Sun-Young, Kim Tae Jun, Hong Sung Noh, Kim Young-Ho, Lee Soo-Youn
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Department of Laboratory Medicine, Green Cross Laboratories, Yongin, Gyeonggi, Republic of Korea.
Br J Clin Pharmacol. 2020 Nov;86(11):2302-2313. doi: 10.1111/bcp.14339. Epub 2020 Jun 1.
This study explores the effects of various genetic polymorphisms in candidate genes on thiopurine metabolism and toxicity in adult patients with Crohn's disease in Korea.
A total of 131 adult patients with Crohn's disease receiving thiopurine treatment were included. The TPMT and NUDT15 genes and an additional 116 genetic polymorphisms (in 40 genes and 3 intergenic locations) were screened for genotyping. Among the polymorphisms screened, 91 genetic polymorphisms (in 34 genes and 3 intergenic locations) in addition to TPMT and NUDT15 genotypes were included for statistical analyses to investigate their effects on thiopurine metabolites and adverse outcomes (leukopenia, hepatotoxicity, gastrointestinal intolerance, skin rash and alopecia).
The median duration of thiopurine treatment was 47.0 months (range 6.0-153.4 months). Patient sex, maintenance dose of thiopurine, and use of anti-tumour necrosis factor agents were associated with thiopurine metabolite concentrations (P < .05). In the univariate analysis, the TPMT genotype was associated with 6-thioguanine level (P < .05), although the significance of this did not remain in multivariate analysis. Genetic polymorphisms in the ATIC (rs3821353 and rs16853834), IMPDH2 (rs11706052) and ITPA (rs6139036) genes were associated with thiopurine metabolism (P < .05). Genetic polymorphisms in the ABCC5 (rs8180093) and NUDT15 genotypes were associated with leukopenia (P < .05).
The results of this study may help clinicians to understand the effects of other various polymorphisms in addition to TPMT and NUDP15 in thiopurine metabolism for management of Crohn's disease patients.
本研究探讨候选基因中的各种基因多态性对韩国成年克罗恩病患者硫嘌呤代谢及毒性的影响。
共纳入131例接受硫嘌呤治疗的成年克罗恩病患者。对硫嘌呤甲基转移酶（TPMT）和NUDT15基因以及另外116个基因多态性位点（位于40个基因和3个基因间区域）进行基因分型筛查。在筛查的多态性位点中，除TPMT和NUDT15基因分型外，另外91个基因多态性位点（位于34个基因和3个基因间区域）纳入统计分析，以研究它们对硫嘌呤代谢产物及不良结局（白细胞减少、肝毒性、胃肠道不耐受、皮疹和脱发）的影响。
硫嘌呤治疗的中位持续时间为47.0个月（范围6.0 - 153.4个月）。患者性别、硫嘌呤维持剂量及抗肿瘤坏死因子药物的使用与硫嘌呤代谢产物浓度相关（P < 0.05）。单因素分析中，TPMT基因分型与6 - 硫鸟嘌呤水平相关（P < 0.05），尽管在多因素分析中该相关性未持续存在。ATIC基因（rs3821353和rs16853834）、肌苷 - 5'-单磷酸脱氢酶2（IMPDH2）基因（rs11706052）和次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶（ITPA）基因（rs6139036）中的基因多态性与硫嘌呤代谢相关（P < 0.05）。ABCC5基因（rs8180093）中的基因多态性和NUDT15基因分型与白细胞减少相关（P < 0.05）。
本研究结果可能有助于临床医生了解除TPMT和NUDP15外其他各种多态性在硫嘌呤代谢中对克罗恩病患者管理的影响。
