Kim Sun-Young, Shin Jin-Hong, Park Jin-Sung, Kang Sa-Yoon, Nam Tai-Seung, Kim Jong Kuk, Park Ki-Jong, Huh So-Young, Oh Ji Seon, Kang Boram, Kim Dae-Seong
Department of Neurology, University of Ulsan, College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea.
Department of Neurology, Pusan National University, Yangsan Hospital, Yangsan, Republic of Korea.
J Neurol Sci. 2017 Jul 15;378:64-68. doi: 10.1016/j.jns.2017.04.041. Epub 2017 Apr 26.
Azathioprine (AZA)-induced leukopenia is a relatively common complication in Korean patients. In addition to variation in TPMT (thiopurine S-methyltransferase), the NUDT15 p.R139C variant was recently identified to have a strong association with AZA-induced leukopenia. We investigated these associations in Korean patients undergoing AZA treatment with various neurological diseases. Among 84 enrolled patients, 20 (23.8%; 7 early, 13 late) exhibited leukopenia. The NUDT15 p.R139C variant was associated with leukopenia (OR: 11.844, 95% CI 3.984-36.024, p=1.327 × 10). The allelic frequency of NUDT15 p.R139C was as high as 10.7% and the frequency of the C/C, C/T, and T/T genotypes was 84.5, 10.7, and 5.9%, respectively. All T/T homozygous patients (5/5) developed early severe-grade leukopenia (white blood cells <1000mm) and severe alopecia. NUDT15 p.R139C was strongly associated with early leukopenia and severe alopecia (OR for early leukopenia: 107.624, 95% CI 18.857-614.250, p=1.403 × 10, OR for severe alopecia: 77.152, 95% CI 17.378-342.526, p=1.101 × 10). The sensitivity and specificity for predicting AZA-induced early leukopenia were 85.7% and 92.2%, respectively. Therefore, the NUDT15 p.R139C variant is common and strongly associated with AZA-induced early leukopenia and severe alopecia in Korean patients with various neurological diseases.
硫唑嘌呤（AZA）诱导的白细胞减少症在韩国患者中是一种相对常见的并发症。除了硫嘌呤S-甲基转移酶（TPMT）存在变异外，最近还发现NUDT15 p.R139C变异与AZA诱导的白细胞减少症密切相关。我们对接受AZA治疗的各种神经系统疾病韩国患者中的这些关联进行了研究。在84名入组患者中，20名（23.8%；7名早期，13名晚期）出现白细胞减少症。NUDT15 p.R139C变异与白细胞减少症相关（比值比：11.844，95%置信区间3.984 - 36.024，p = 1.327×10）。NUDT15 p.R139C的等位基因频率高达10.7%，C/C、C/T和T/T基因型的频率分别为84.5%、10.7%和5.9%。所有T/T纯合患者（5/5）均出现早期重度白细胞减少症（白细胞<1000/mm）和严重脱发。NUDT15 p.R139C与早期白细胞减少症和严重脱发密切相关（早期白细胞减少症的比值比：107.624，95%置信区间18.857 - 614.250，p = 1.403×10，严重脱发的比值比：77.152，95%置信区间17.378 - 342.526，p = 1.101×10）。预测AZA诱导的早期白细胞减少症的敏感性和特异性分别为85.7%和92.2%。因此，NUDT15 p.R139C变异在患有各种神经系统疾病的韩国患者中很常见，且与AZA诱导的早期白细胞减少症和严重脱发密切相关。
