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Nudix Hydroxylase 15 Mutations Strongly Predict Thiopurine-Induced Leukopenia Across Different Asian Ethnicities: Implications for Screening in a Diverse Population

BACKGROUND AND AIMS: Thiopurines, which are immunosuppressive drugs for maintaining remission for inflammatory bowel disease, are known to cause myelotoxicity in patients with Nudix Hydroxylase 15 (NUDT15) genetic variants in some Asian countries with monoethnic populations. We aimed to investigate...

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Autores principales: Khoo, Xin-Hui, Wong, Shin Yee, Ibrahim, Nik Razima Wan, Ng, Ruey Terng, Chew, Kee Seang, Lee, Way Seah, Wong, Zhi Qin, Raja Ali, Raja Affend, Shahrani, Shahreedhan, Leow, Alex Hwong-Ruey, Hilmi, Ida Normiha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9388767/
https://www.ncbi.nlm.nih.gov/pubmed/35991642
http://dx.doi.org/10.3389/fmed.2022.880937
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author Khoo, Xin-Hui
Wong, Shin Yee
Ibrahim, Nik Razima Wan
Ng, Ruey Terng
Chew, Kee Seang
Lee, Way Seah
Wong, Zhi Qin
Raja Ali, Raja Affend
Shahrani, Shahreedhan
Leow, Alex Hwong-Ruey
Hilmi, Ida Normiha
author_facet Khoo, Xin-Hui
Wong, Shin Yee
Ibrahim, Nik Razima Wan
Ng, Ruey Terng
Chew, Kee Seang
Lee, Way Seah
Wong, Zhi Qin
Raja Ali, Raja Affend
Shahrani, Shahreedhan
Leow, Alex Hwong-Ruey
Hilmi, Ida Normiha
author_sort Khoo, Xin-Hui
collection PubMed
description BACKGROUND AND AIMS: Thiopurines, which are immunosuppressive drugs for maintaining remission for inflammatory bowel disease, are known to cause myelotoxicity in patients with Nudix Hydroxylase 15 (NUDT15) genetic variants in some Asian countries with monoethnic populations. We aimed to investigate the association of NUDT15 variants with leukopenia in a multiethnic population in Southeast Asia. METHODS: Patients with a confirmed diagnosis of inflammatory bowel disease were recruited. We collected demographic and clinical characteristics and whole blood counts before and after initiating thiopurines. Thiopurine S-methyltransferase (TPMT) and NUDT15 genotypes were analyzed with the single nucleotide polymorphisms (SNPs) genotyping assay. Leukopenia was defined as a white blood cell (WBC) count < 3,000/μl. RESULTS: In this study, 19 (18.6%) of the 102 patients who had adequate thiopurine therapy experienced leukopenia, 11 patients (57.9%) had NUDT15 c.415C > T variants, 2 patients (10.5%) had NUDT15 c.52G > A variants while one (5.3%) had a TPMT variation. Individually, NUDT15 c.415C > T had a sensitivity and specificity of 57.9% and 94.0% (odds ratio [OR] = 21.45, 95% CI 5.94–77.41, p < 0.001), respectively, for predicting thiopurine-induced leukopenia, while NUDT15 c.52G > A was only observed in patients with leukopenia. As compared with patients with wild-type NUDT15, both NUDT15 variations had a combined sensitivity and specificity of 68.4% and 94%, respectively (OR = 33.80, 95% CI 8.99–127.05, p < 0.001), for predicting thiopurine-induced leukopenia as well as a shorter onset to leukopenia (median onset [months] 2.0 vs. 5.5; p = 0.045). Sub-group analysis showed that both NUDT15 variations were strongly associated with leukopenia among the Chinese and Indians but not among the Malays. CONCLUSION: Nudix Hydroxylase 15 variants strongly predicted thiopurine-induced leukopenia across a multiethnic Southeast Asian population, particularly among the Chinese and Indians.
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spelling pubmed-93887672022-08-20 Nudix Hydroxylase 15 Mutations Strongly Predict Thiopurine-Induced Leukopenia Across Different Asian Ethnicities: Implications for Screening in a Diverse Population Khoo, Xin-Hui Wong, Shin Yee Ibrahim, Nik Razima Wan Ng, Ruey Terng Chew, Kee Seang Lee, Way Seah Wong, Zhi Qin Raja Ali, Raja Affend Shahrani, Shahreedhan Leow, Alex Hwong-Ruey Hilmi, Ida Normiha Front Med (Lausanne) Medicine BACKGROUND AND AIMS: Thiopurines, which are immunosuppressive drugs for maintaining remission for inflammatory bowel disease, are known to cause myelotoxicity in patients with Nudix Hydroxylase 15 (NUDT15) genetic variants in some Asian countries with monoethnic populations. We aimed to investigate the association of NUDT15 variants with leukopenia in a multiethnic population in Southeast Asia. METHODS: Patients with a confirmed diagnosis of inflammatory bowel disease were recruited. We collected demographic and clinical characteristics and whole blood counts before and after initiating thiopurines. Thiopurine S-methyltransferase (TPMT) and NUDT15 genotypes were analyzed with the single nucleotide polymorphisms (SNPs) genotyping assay. Leukopenia was defined as a white blood cell (WBC) count < 3,000/μl. RESULTS: In this study, 19 (18.6%) of the 102 patients who had adequate thiopurine therapy experienced leukopenia, 11 patients (57.9%) had NUDT15 c.415C > T variants, 2 patients (10.5%) had NUDT15 c.52G > A variants while one (5.3%) had a TPMT variation. Individually, NUDT15 c.415C > T had a sensitivity and specificity of 57.9% and 94.0% (odds ratio [OR] = 21.45, 95% CI 5.94–77.41, p < 0.001), respectively, for predicting thiopurine-induced leukopenia, while NUDT15 c.52G > A was only observed in patients with leukopenia. As compared with patients with wild-type NUDT15, both NUDT15 variations had a combined sensitivity and specificity of 68.4% and 94%, respectively (OR = 33.80, 95% CI 8.99–127.05, p < 0.001), for predicting thiopurine-induced leukopenia as well as a shorter onset to leukopenia (median onset [months] 2.0 vs. 5.5; p = 0.045). Sub-group analysis showed that both NUDT15 variations were strongly associated with leukopenia among the Chinese and Indians but not among the Malays. CONCLUSION: Nudix Hydroxylase 15 variants strongly predicted thiopurine-induced leukopenia across a multiethnic Southeast Asian population, particularly among the Chinese and Indians. Frontiers Media S.A. 2022-08-05 /pmc/articles/PMC9388767/ /pubmed/35991642 http://dx.doi.org/10.3389/fmed.2022.880937 Text en Copyright © 2022 Khoo, Wong, Ibrahim, Ng, Chew, Lee, Wong, Raja Ali, Shahrani, Leow and Hilmi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Khoo, Xin-Hui
Wong, Shin Yee
Ibrahim, Nik Razima Wan
Ng, Ruey Terng
Chew, Kee Seang
Lee, Way Seah
Wong, Zhi Qin
Raja Ali, Raja Affend
Shahrani, Shahreedhan
Leow, Alex Hwong-Ruey
Hilmi, Ida Normiha
Nudix Hydroxylase 15 Mutations Strongly Predict Thiopurine-Induced Leukopenia Across Different Asian Ethnicities: Implications for Screening in a Diverse Population
title Nudix Hydroxylase 15 Mutations Strongly Predict Thiopurine-Induced Leukopenia Across Different Asian Ethnicities: Implications for Screening in a Diverse Population
title_full Nudix Hydroxylase 15 Mutations Strongly Predict Thiopurine-Induced Leukopenia Across Different Asian Ethnicities: Implications for Screening in a Diverse Population
title_fullStr Nudix Hydroxylase 15 Mutations Strongly Predict Thiopurine-Induced Leukopenia Across Different Asian Ethnicities: Implications for Screening in a Diverse Population
title_full_unstemmed Nudix Hydroxylase 15 Mutations Strongly Predict Thiopurine-Induced Leukopenia Across Different Asian Ethnicities: Implications for Screening in a Diverse Population
title_short Nudix Hydroxylase 15 Mutations Strongly Predict Thiopurine-Induced Leukopenia Across Different Asian Ethnicities: Implications for Screening in a Diverse Population
title_sort nudix hydroxylase 15 mutations strongly predict thiopurine-induced leukopenia across different asian ethnicities: implications for screening in a diverse population
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9388767/
https://www.ncbi.nlm.nih.gov/pubmed/35991642
http://dx.doi.org/10.3389/fmed.2022.880937
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