NUDT15基因变异对中国汉族皮肤病患者中性粒细胞减少症的预测价值：一项单中心观察性研究
Predictive Value of NUDT15 Variants on Neutropenia Among Han Chinese Patients with Dermatologic Diseases: A Single-Center Observational Study.
作者信息
Huang Po-Wei, Tseng Yu-Hsian, Tsai Tsen-Fang
机构信息
Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan South Road, Taipei, Taiwan.
出版信息
Dermatol Ther (Heidelb). 2020 Apr;10(2):263-271. doi: 10.1007/s13555-020-00360-4. Epub 2020 Feb 15.
INTRODUCTION
Azathioprine is a synthetic purine analogue derived from 6-mercaptopurine which acts by disrupting nucleic acid synthesis and interfering with T cell activation. It is effective in dermatology diseases related to the immune system. However, its side effects, including severe neutropenia, kept patients from using it. Mutations in thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphohydrolase (ITPA) genes account for the major genetic polymorphism markers for azathioprine adverse risk factors in Caucasians, but not in Asians. The predictive value of the nucleoside diphosphate-linked moiety X motif 15 gene (NUDT15) has been studied in various diseases among different populations. The aim of our study was to determine the contribution of NUDT15 mutations in azathioprine-induced neutropenia in Han Chinese patients with dermatologic diseases.
METHODS
The study enrolled all consecutive patients, older than 13 years old, with dermatological diseases currently treated orally with azathioprine in our clinic. Samples were also collected from patients with documented leukopenia in our prior study that examined the association between TPMT, ITPA, and neutropenia after informed reconsent. Complete blood count, differential count, and hepatic and renal function were checked regularly. The DNA samples for NUDT15 genotype were obtained from the patients.
RESULTS
In total, we enrolled 56 patients (39 male, 17 female). The NUDT15 genotypes are mostly C/C (N = 36, 64.29%). Heterozygous variant (C/T) accounts for 30.36% (N = 17) and homozygous variant (T/T) accounts for 5.36% (N = 3). Among these patients, 15 patients (26.79%) developed neutropenia, including all three patients carry homozygous variant (T/T). The age-, sex-, and dose-adjusted risk of heterozygous variant compared to wild type is 9.383 (95% CI 1.32-66.96).
CONCLUSIONS
Pretreatment screening of NUDT15 might reduce the chance of azathioprine-induced neutropenia in Han Chinese patients with dermatologic diseases.
引言
硫唑嘌呤是一种由6-巯基嘌呤衍生而来的合成嘌呤类似物，其作用机制是破坏核酸合成并干扰T细胞活化。它对与免疫系统相关的皮肤病有效。然而，其副作用，包括严重的中性粒细胞减少症，使患者无法使用它。硫嘌呤甲基转移酶（TPMT）和肌苷三磷酸焦磷酸水解酶（ITPA）基因的突变是白种人硫唑嘌呤不良风险因素的主要遗传多态性标志物，但在亚洲人中并非如此。核苷二磷酸连接部分X基序15基因（NUDT15）的预测价值已在不同人群的各种疾病中进行了研究。我们研究的目的是确定NUDT15突变在汉族皮肤病患者硫唑嘌呤诱导的中性粒细胞减少症中的作用。
方法
本研究纳入了所有年龄大于13岁、目前在我们诊所口服硫唑嘌呤治疗皮肤病的连续患者。在我们之前一项研究中，在获得知情同意后，也从有白细胞减少记录的患者中采集了样本，该研究检查了TPMT、ITPA与中性粒细胞减少之间的关联。定期检查全血细胞计数、分类计数以及肝肾功能。从患者中获取用于NUDT15基因分型的DNA样本。
结果
我们总共纳入了56例患者（39例男性，17例女性）。NUDT15基因型大多为C/C（N = 36，64.29%）。杂合变异型（C/T）占30.36%（N = 17），纯合变异型（T/T）占5.36%（N = 3）。在这些患者中，15例（26.79%）出现了中性粒细胞减少症，包括所有3例携带纯合变异型（T/T）的患者。与野生型相比，杂合变异型经年龄、性别和剂量调整后的风险为9.383（95%CI 1.32 - 66.96）。
结论
对汉族皮肤病患者进行NUDT15预处理筛查可能会降低硫唑嘌呤诱导的中性粒细胞减少症的发生几率。
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