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

Taiwan/Asian Severe Cutaneous Adverse Reaction Consortium

doi:10.1002/cpt.2716

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

Taiwan/Asian Severe Cutaneous Adverse Reaction Consortium

Research output: Contribution to journal › Journal Article › peer-review

12 Scopus citations

Abstract

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 × 10⁻²⁵, odds ratio (OR) = 21.7, 95% confidence interval (95% CI) = 12.1–38.8) and NUDT15 rs746071566 (P = 4.2 × 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 × 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.

Original language	English
Pages (from-to)	1079-1087
Number of pages	9
Journal	Clinical Pharmacology and Therapeutics
Volume	112
Issue number	5
DOIs	https://doi.org/10.1002/cpt.2716
State	Published - 11 2022

Bibliographical note

Publisher Copyright:
© 2022 Chang Gung Memorial Hospital. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

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10.1002/cpt.2716

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@article{84d96fb2c9ba4f91b2bdf2cb5678bbf7,

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

abstract = "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 × 10−25, odds ratio (OR) = 21.7, 95\% confidence interval (95\% CI) = 12.1–38.8) and NUDT15 rs746071566 (P = 4.2 × 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 × 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.",

author = "\{Taiwan/Asian Severe Cutaneous Adverse Reaction Consortium\} and Wang, \{Chuang Wei\} and Chi, \{Min Hui\} and Tsai, \{Tsen Fang\} and Yu, \{Kuang Hui\} and Kao, \{Hsiao Wen\} and Chen, \{Hsiang Cheng\} and Chen, \{Chun Bing\} and Lu, \{Chun Wei\} and Chen, \{Wei Ti\} and Chang, \{Ya Ching\} and Chang, \{Chih Jung\} and Chang, \{Yun Ting\} and \{Jan Wu\}, \{Yeong Jian\} and Chang, \{Chee Jen\} and Huang, \{Yu Huei\} and Ng, \{Chau Yee\} and Huang, \{Po Wei\} and Lin, \{Yu Jr\} and Hui, \{Rosaline Chung Yee\} and Chung, \{Wen Hung\}",

note = "Publisher Copyright: {\textcopyright} 2022 Chang Gung Memorial Hospital. Clinical Pharmacology \& Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.",

year = "2022",

month = nov,

doi = "10.1002/cpt.2716",

language = "英语",

volume = "112",

pages = "1079--1087",

journal = "Clinical Pharmacology and Therapeutics",

issn = "0009-9236",

publisher = "Wiley-Blackwell",

number = "5",

}

TY - JOUR

T1 - Implementation of NUDT15 Genotyping to Prevent Azathioprine-Induced Leukopenia for Patients With Autoimmune Disorders in Chinese Population

AU - Taiwan/Asian Severe Cutaneous Adverse Reaction Consortium

AU - Wang, Chuang Wei

AU - Chi, Min Hui

AU - Tsai, Tsen Fang

AU - Yu, Kuang Hui

AU - Kao, Hsiao Wen

AU - Chen, Hsiang Cheng

AU - Chen, Chun Bing

AU - Lu, Chun Wei

AU - Chen, Wei Ti

AU - Chang, Ya Ching

AU - Chang, Chih Jung

AU - Chang, Yun Ting

AU - Jan Wu, Yeong Jian

AU - Chang, Chee Jen

AU - Huang, Yu Huei

AU - Ng, Chau Yee

AU - Huang, Po Wei

AU - Lin, Yu Jr

AU - Hui, Rosaline Chung Yee

AU - Chung, Wen Hung

N1 - Publisher Copyright: © 2022 Chang Gung Memorial Hospital. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

PY - 2022/11

Y1 - 2022/11

N2 - 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 × 10−25, odds ratio (OR) = 21.7, 95% confidence interval (95% CI) = 12.1–38.8) and NUDT15 rs746071566 (P = 4.2 × 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 × 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.

AB - 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 × 10−25, odds ratio (OR) = 21.7, 95% confidence interval (95% CI) = 12.1–38.8) and NUDT15 rs746071566 (P = 4.2 × 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 × 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.

UR - https://www.scopus.com/pages/publications/85136489124

U2 - 10.1002/cpt.2716

DO - 10.1002/cpt.2716

M3 - 文章

C2 - 35869597

AN - SCOPUS:85136489124

SN - 0009-9236

VL - 112

SP - 1079

EP - 1087

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

IS - 5

ER -

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

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