Zhang A L, Yang J, Wang H, Lu J L, Tang S, Zhang X J
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe Road, Erqi District, 450052, Zhengzhou, People's Republic of China.
Ir J Med Sci. 2018 Feb;187(1):145-153. doi: 10.1007/s11845-017-1608-x. Epub 2017 May 3.
Thiopurines, commonly used to treat autoimmune conditions and cancer, can be limited by life-threatening leucopenia. However, whether NUDT15 (nucleoside diphosphate-linked moiety X-type motif 15) is associated with thiopurine-induced leucopenia in Asians is controversial.
Relevant studies in English that were published until July 10, 2016 were identified through PubMed, EMbase, and other web knowledge databases. Study quality was assessed according to the Newcastle-Ottawa Scale (NOS) criteria. Summary risk ratio (RR) and 95% confidence intervals (CI) were estimated based on a fixed-effects model or a random-effects model, depending on the absence or presence of significant heterogeneity.
Seven studies of 1138 patients met our inclusion criteria. Random-effects model meta-analysis provided evidence that T carriers of NUDT15 c.415C>T were significantly correlated with high incidences of thiopurine-induced leukocytopenia [CT + TT vs. CC: RR = 3.79, 95%CI (2.64 ~ 5.44), P < 0.00001]. This correlation was especially strong in TT patients, where it was found to be significantly increased by 6.54-fold compared with CC patients [TT vs. CC: RR = 6.54, 95%CI (3.34 ~ 12.82), P < 0.00001]. We also found that the NUDT15 c.415C>T variant was common in Asians and Hispanics, but rare in Europeans and Africans; the frequency of the NUDT15 c.415C>T distribution varied substantially by race/ethnicity.
The results of this meta-analysis confirm that NUDT15 c.415C>T may be an important predictor of thiopurine-induced leukocytopenia in Asians. Genotype targeting of NUDT15 c.415C>T before initiating thiopurine treatment may be useful to limit leukocytopenia.
硫嘌呤常用于治疗自身免疫性疾病和癌症，但其可能因危及生命的白细胞减少而受到限制。然而，在亚洲人群中，NUDT15（核苷二磷酸连接的X型基序15）是否与硫嘌呤诱导的白细胞减少相关仍存在争议。
通过PubMed、EMbase和其他网络知识数据库检索截至2016年7月10日发表的英文相关研究。根据纽卡斯尔-渥太华量表（NOS）标准评估研究质量。根据是否存在显著异质性，基于固定效应模型或随机效应模型估计汇总风险比（RR）和95%置信区间（CI）。
1138例患者的7项研究符合纳入标准。随机效应模型荟萃分析提供的证据表明，NUDT15基因c.415C>T的T等位基因携带者与硫嘌呤诱导的白细胞减少的高发生率显著相关[CT+TT与CC相比：RR=3.79，95%CI（2.645.44），P<0.00001]。这种相关性在TT患者中尤为明显，与CC患者相比，其发生率显著增加了6.54倍[TT与CC相比：RR=6.54，95%CI（3.3412.82），P<0.00001]。我们还发现，NUDT15基因c.415C>T变异在亚洲人和西班牙裔中很常见，但在欧洲人和非洲人中很少见；NUDT15基因c.415C>T的分布频率因种族/民族而异。
这项荟萃分析的结果证实，NUDT15基因c.415C>T可能是亚洲人群中硫嘌呤诱导的白细胞减少的重要预测指标。在开始硫嘌呤治疗前对NUDT15基因c.415C>T进行基因型靶向检测，可能有助于减少白细胞减少的发生。
