*Department of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China; †Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; ‡Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; §Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China; ‖Department of Gastroenterology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China; and ¶Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Inflamm Bowel Dis. 2017 Sep;23(9):1592-1599. doi: 10.1097/MIB.0000000000001148.
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.
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.
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, P = 4.74 × 10 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).
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.
NUDT15 c.415C>T 是我们中心在中国炎症性肠病（IBD）患者中发现的一种新型硫嘌呤诱导白细胞减少的遗传标志物。为了验证这一发现，需要进行大规模的队列研究。同时，新发现的 NUDT15 编码变异（c.36_37insGGAGTC 和 c.52G>A）尚未在 IBD 患者中进行研究。我们旨在进一步确认 3 种 NUDT15 变异（c.415C>T、c.36_37insGGAGTC 和 c.52G>A）对中国 IBD 患者硫嘌呤诱导白细胞减少的影响。
从 4 家三级医院招募至少服用 2 周硫嘌呤的患者。收集临床数据。采用聚合酶链反应-RFLP 和测序法确定 NUDT15 基因型。分析变异与白细胞减少之间的相互作用。
共纳入 732 例患者，其中 177 例（24.3%）发生白细胞减少。NUDT15 c.415C>T、c.36_37insGGAGTC 和 c.52G>A 与硫嘌呤诱导的白细胞减少密切相关（P = 1.81×10、P = 4.74×10 和 P = 0.04），而硫嘌呤 S-甲基转移酶基因型无相关性（P = 0.25）。NUDT15 c.415C>T 的预测敏感性为 49.2%，当与 c.36_37insGGAGTC 和 c.52G>A 联合分析时，敏感性增加至 55.4%。值得注意的是，不仅 NUDT15 c.415C>T 纯合子，而且同时携带 c.415C>T 和 c.52G>A 的杂合子均发生早期白细胞减少。NUDT15 c.415C>T 携带者的中位数剂量明显低于野生型（P<0.001）。
我们证实 NUDT15 c.415C>T、c.36_37insGGAGTC 和 c.52G>A 变异是硫嘌呤诱导白细胞减少的危险因素。联合检测 3 种变异可提高硫嘌呤诱导白细胞减少的预测敏感性，并有助于区分中国 IBD 患者 c.415C>T 杂合子的早期白细胞减少。通过 NUDT15 变异进行治疗监测可能是个体化治疗的一种有前途的方法。
