Combined Detection of NUDT15 Variants Could Highly Predict Thiopurine-induced Leukopenia in Chinese Patients with Inflammatory Bowel Disease: A Multicenter Analysis

被引：70

作者：

Chao, Kang ^{[1
]}

Wang, Xueding ^{[2
]}

Cao, Qian ^{[3
]}

Qian, Jiaming ^{[4
]}

Wu, Kaichun ^{[5
]}

Zhu, Xia ^{[1
,2
]}

Yang, Hong ^{[4
]}

Liang, Jie ^{[5
]}

Lin, Lang ^{[1
]}

Huang, Zicheng ^{[1
]}

Zhang, Yu ^{[3
]}

Huang, Yibiao ^{[3
]}

Sun, Yinghao ^{[4
]}

Xue, Xianmin ^{[5
]}

Huang, Min ^{[2
]}

Hu, Pinjin ^{[1
]}

Lan, Ping ^{[6
]}

Gao, Xiang ^{[1
]}

机构：

[1] Sun Yat Sen Univ, Affiliated Hosp 6, Dept Gastroenterol, Guangdong Prov Key Lab Colorectal & Pelv Floor Di, Guangzhou, Guangdong, Peoples R China

[2] Sun Yat Sen Univ, Inst Clin Pharmacol, Sch Pharmaceut Sci, Guangzhou, Guangdong, Peoples R China

[3] Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Gastroenterol, Hangzhou, Zhejiang, Peoples R China

[4] Peking Union Med Coll Hosp, Dept Gastroenterol, Beijing, Peoples R China

[5] Fourth Mil Med Univ, Xijing Hosp, Dept Gastroenterol, Xian, Shaanxi, Peoples R China

[6] Sun Yat Sen Univ, Affiliated Hosp 6, Dept Colorectal Surg, Guangzhou, Guangdong, Peoples R China

来源：

INFLAMMATORY BOWEL DISEASES | 2017年 / 23卷 / 09期

基金：

中国国家自然科学基金;

关键词：

inflammatory bowel disease; NUDT15; TPMT; leukopenia; S-METHYLTRANSFERASE; CROHNS-DISEASE; JAPANESE PATIENTS; LONG-TERM; AZATHIOPRINE; PHARMACOGENETICS; POLYMORPHISMS; GENOTYPE; THERAPY; 6-MERCAPTOPURINE;

D O I：

10.1097/MIB.0000000000001148

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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 x 10(-20), P = 4.74 x 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.

引用

页码：1592 / 1599

页数：8

共 32 条

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