Implementation of NUDT15 Genotyping to Prevent Azathioprine-Induced Leukopenia for Patients With Autoimmune Disorders in Chinese Population

被引：5

作者：

Wang, Chuang-Wei ^{[1
,2
,3
,4
,5
,6
,7
]}

Chi, Min-Hui ^{[1
,2
,3
,7
,8
]}

Tsai, Tsen-Fang ^{[9
,10
]}

Yu, Kuang-Hui ^{[7
,11
]}

Kao, Hsiao-Wen ^{[7
,12
]}

Chen, Hsiang-Cheng ^{[13
]}

Chen, Chun-Bing ^{[1
,2
,3
,5
,6
,7
,14
,15
,16
]}

Lu, Chun-Wei ^{[1
,2
,3
,6
,7
,15
,16
]}

Chen, Wei-Ti ^{[1
,2
,3
,6
,7
]}

Chang, Ya-Ching ^{[1
,2
,3
,7
]}

Chang, Chih-Jung ^{[1
,2
,3
,17
,18
,19
]}

Chang, Yun-Ting ^{[20
]}

Wu, Yeong-Jian Jan ^{[7
,21
]}

Chang, Chee-Jen ^{[22
]}

Huang, Yu Huei ^{[1
,2
,3
,7
]}

Ng, Chau-Yee ^{[1
,2
,3
,7
,16
]}

Huang, Po-Wei ^{[9
,10
,23
]}

Lin, Yu-, Jr. ^{[22
]}

Hui, Rosaline Chung-Yee ^{[1
,2
,3
,7
]}

Chung, Wen-Hung ^{[1
,2
,3
,4
,5
,6
,7
,14
,15
,24
,25
,26
]}

机构：

[1] Chang Gung Mem Hosp, Drug Hypersensit Clin & Res Ctr, Dept Dermatol, Linkou, Taiwan

[2] Chang Gung Mem Hosp, Drug Hypersensit Clin & Res Ctr, Dept Dermatol, Taipei, Taiwan

[3] Chang Gung Mem Hosp, Drug Hypersensit Clin & Res Ctr, Dept Dermatol, Keelung, Taiwan

[4] Chang Gung Mem Hosp, Canc Vaccine & Immune Cell Therapy Core Lab, Linkou, Taiwan

[5] Chang Gung Univ, Chang Gung Immunol Consortium, Chang Gung Mem Hosp, Taoyuan, Taiwan

[6] Xiamen Chang Gung Hosp, Dept Dermatol, Xiamen, Peoples R China

[7] Chang Gung Univ, Coll Med, Taoyuan, Taiwan

[8] Natl Taiwan Univ, Coll Med, Inst Mol Med, Taipei, Taiwan

[9] Natl Taiwan Univ Hosp, Dept Dermatol, Taipei, Taiwan

[10] Natl Taiwan Univ, Dept Dermatol, Coll Med, Taipei, Taiwan

[11] Chang Gung Mem Hosp, Dept Internal Med, Div Rheumatol, Linkou, Taiwan

[12] Chang Gung Mem Hosp, Dept Internal Med, Div Hematol Oncol, Linkou, Taiwan

[13] Triserv Gen Hosp, Dept Med, Div Rheumatol Immunol & Allergy, Taipei, Taiwan

[14] Chang Gung Mem Hosp, Whole Genome Res Core Lab Human Dis, Keelung, Taiwan

[15] Chang Gung Mem Hosp, Immune Oncol Ctr Excellence, Linkou, Taiwan

[16] Chang Gung Univ, Coll Med, Grad Inst Clin Med Sci, Taoyuan, Taiwan

[17] Xiamen Chang Gung Hosp, Med Res Ctr, Xiamen, Fujian, Peoples R China

[18] Xiamen Chang Gung Hosp, Xiamen Chang Gung Allergol Consortium, Xiamen, Fujian, Peoples R China

[19] Huaqiao Univ, Sch Med, Quanzhou, Fujian, Peoples R China

[20] Taipei Vet Gen Hosp, Dept Dermatol, Taipei, Taiwan

[21] Chang Gung Mem Hosp, Dept Med, Div Allergy Immunol & Rheumatol, Keelung, Taiwan

[22] Chang Gung Univ, Res Serv Ctr Hlth Informat, Taoyuan, Taiwan

[23] Natl Taiwan Univ, Dept Surg, Sect Dermatol, Canc Ctr, Taipei, Taiwan

[24] Tsinghua Univ, Beijing Tsinghua Chang Gung Hosp, Sch Clin Med, Dept Dermatol, Beijing, Peoples R China

[25] Shanghai Jiao Tong Univ, Ruijin Hosp, Sch Med, Dept Dermatol, Shanghai, Peoples R China

[26] Chang Gung Mem Hosp, Genom Med Core Lab, Linkou, Taiwan

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2022年 / 112卷 / 05期

关键词：

VARIANT; MYELOSUPPRESSION; SUSCEPTIBILITY; FEATURES; MARKER; COMMON;

D O I：

10.1002/cpt.2716

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Azathioprine (AZA) is commonly used for many autoimmune disorders; however, the limitation of its clinical use is due to potential toxicities, including severe leukopenia. Recent studies have identified genetic NUDT15 variants strongly associated with AZA-induced leukopenia in Asian patients. This study aimed to investigate the strength of above genetic association and evaluate the usefulness of prospective screening of the NUDT15 variants to prevent AZA-induced leukopenia in Chinese patients. AZA-induced leukopenia in patients with autoimmune disorders were enrolled from multiple medical centers in Taiwan/China between 2012 and 2017 to determine the strength of genetic association of NUDT15 or TPMT variants by whole exome sequencing (WES). Furthermore, a prospective study was conducted between 2018 and 2021 to investigate the incidence of AZA-induced leukopenia with and without genetic screening. The WES result showed the genetic variants of NUDT15 R139C (rs116855232) (P = 3.7 x 10(-25), odds ratio (OR) = 21.7, 95% confidence interval (95% CI) = 12.1-38.8) and NUDT15 rs746071566 (P = 4.2 x 10(-9), OR = 7.1, 95% CI = 3.7-13.7), but not TPMT, were associated with AZA-induced leukopenia and NUDT15 R139C variant shows the highest sensitivity with 92.5%. Furthermore, the targeted screening of 1,013 participants for NUDT15 R139C enabled those identified as carriers to use alternative immunosuppressants. This strategy resulted in a significant decrease in the incidence of AZA-induced leukopenia compared with historical incidence (incidence rate = from 7.6% decreased to 0.4%; P = 9.3 x 10(-20)). In conclusion, the NUDT15 R139C variant was strongly associated with AZA-induced leukopenia in Chinese patients. The genetic screening of NUDT15 R139C followed by use of alternative immunosuppressants in identified carriers effectively decreased the incidence of AZA leukopenia for patients with autoimmune disorders.

引用

页码：1079 / 1087

页数：9

共 45 条

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