Combined Detection of NUDT15 Variants Could Highly Predict Thiopurine-induced Leukopenia in Chinese Patients with Inflammatory Bowel Disease: A Multicenter Analysis
Combined Detection of NUDT15 Variants Could Highly Predict Thiopurine-induced Leukopenia in Chinese Patients with Inflammatory Bowel Disease: A Multicenter Analysis
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联合检测 NUDT15 变异体可高度预测中国炎症性肠病患者硫嘌呤诱导的白细胞减少症：多中心分析
DOI：
10.1097/mib.0000000000001148
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发表时间：
2017-09-01
影响因子：
4.9
通讯作者：
Gao, Xiang
中科院分区：
文献类型：
--
作者：
Chao, Kang;Wang, Xueding;Gao, Xiang
背景资料：NUDT 15 c.415C>T是一个新的遗传标记，在我们的中心证实了硫嘌呤诱导的白细胞减少症在中国炎症性肠病（IBD）。为了验证，需要进行大型队列研究。同时，新发现的NUDT 15编码变体（c.36_37insGGAGTC和c.52 G>A）尚未在IBD患者中进行研究。我们的目的是进一步证实3种NUDT 15变体（c.415C>T、c.36_37insGGAGTC和c.52G>A）对中国IBD患者中硫嘌呤诱导的白细胞减少症的影响。方法：从4家三级医院招募至少2周的硫嘌呤处方患者。收集临床数据。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）和测序法检测NUDT 15基因型。分析变异体与白细胞减少症之间的相互作用。结果：共纳入732例患者，其中177例（24.3%）发生白细胞减少。NUDT 15 c.415C>T、c.36_37insGGAGTC和c.52G>A与巯嘌呤诱导的白细胞减少症有很强的相关性（分别为P = 1.81 × 10−20、P = 4.74 × 10−8和P = 0.04），而与巯嘌呤S-甲基转移酶基因型无关（P = 0.25）。NUDT 15 c.415C>T的预测敏感性为49.2%，而与c.36_37insGGAGTC和c.52G>A联合分析，其预测敏感性提高到55.4%。值得注意的是，不仅NUDT 15 c.415C>T的纯合子，而且同时携带c.415C>T和c.52G>A的杂合子也发生早期白细胞减少症。NUDT 15 c.415 C>T携带者的中位剂量显著低于野生型（P < 0.001）。结论：我们证实NUDT 15 c.415C>T、c.36_37insGGAGTC和c.52G>A变异体是硫嘌呤诱导的白细胞减少症的危险因素。联合检测c.415C>T基因突变可提高预测硫嘌呤所致白细胞减少症的敏感性，有助于鉴别中国IBD患者c.415C>T杂合子的早期白细胞减少症。NUDT 15变体的治疗监测在个体化治疗中可能是有希望的。
Background: NUDT15 c.415C>T was a novel genetic marker confirmed in our center for thiopurine-induced leukopenia in Chinese inflammatory bowel disease (IBD). For validation, a large cohort study is needed. Meanwhile, the newly discovered NUDT15 coding variants (c.36_37insGGAGTC and c.52 G>A) have not been studied in patients with IBD. We aimed to further confirm the influence of 3 NUDT15 variants (c.415C>T, c.36_37insGGAGTC, and c.52G>A) on thiopurine-induced leukopenia in Chinese patients with IBD. Methods: Patients prescribed on thiopurines for at least 2 weeks were recruited from 4 tertiary hospitals. Clinical data were collected. NUDT15 genotypes were determined with polymerase chain reaction-RFLP and sequencing. The interactions between variants and leukopenia were analyzed. Results: A total of 732 patients were included, 177 (24.3%) of whom developed leukopenia. There were strong associations of NUDT15 c.415C>T, c.36_37insGGAGTC, and c.52G>A with thiopurine-induced leukopenia (P = 1.81 × 10−20, P = 4.74 × 10−8 and P = 0.04, respectively), whereas there was no relevance for thiopurine S-methyltransferase genotypes (P = 0.25). The predictive sensitivity of NUDT15 c.415C>T was 49.2%, whereas it increased to 55.4% when combined analysis with c.36_37insGGAGTC and c.52G>A. Notably, not only the homozygotes with NUDT15 c.415C>T but also the heterozygotes both carrying c.415C>T and c.52G>A developed early leukopenia. The median dosage for NUDT15 c.415C>T carriers was significantly lower than that for wild-type (P < 0.001). Conclusions: We confirmed that NUDT15 c.415C>T, c.36_37insGGAGTC, and c.52G>A variants were risk factors for thiopurine-induced leukopenia. Combined detection of the 3 variants could increase the predictive sensitivity of thiopurine-induced leukopenia and help to distinguish early leukopenia in heterozygote of c.415C>T in Chinese patients with IBD. Treatment monitoring by NUDT15 variants may be promising in individualized therapy.