Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis

Abstract This study aimed to investigate the influence of TPMT*3C, ITPA, NUDT15, and 6-thioguanine nucleotides (6-TGN) on azathioprine (AZA)-induced myelosuppression in Southwest China patients with autoimmune hepatitis (AIH). A total of 113 Chinese patients with AIH receiving AZA maintenance treatm...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Qiang Miao, Lin Yan, Yanhong Zhou, Yi Li, Yuangao Zou, Lanlan Wang, Yangjuan Bai, Junlong Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/afab0be173e54833b6b684fbf1ed459b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:afab0be173e54833b6b684fbf1ed459b
record_format	dspace
spelling	oai:doaj.org-article:afab0be173e54833b6b684fbf1ed459b2021-12-02T14:26:19ZAssociation of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis10.1038/s41598-021-87095-02045-2322https://doaj.org/article/afab0be173e54833b6b684fbf1ed459b2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87095-0https://doaj.org/toc/2045-2322Abstract This study aimed to investigate the influence of TPMT3C, ITPA, NUDT15, and 6-thioguanine nucleotides (6-TGN) on azathioprine (AZA)-induced myelosuppression in Southwest China patients with autoimmune hepatitis (AIH). A total of 113 Chinese patients with AIH receiving AZA maintenance treatment were evaluated. The relevant clinical data of the patients were collected from the hospital information system. Genotyping of TPMT3C(rs1142345), ITPA (rs1127354) and NUDT15(rs116855232) was conducted using a TaqMan double fluorescent probe. The concentration of 6-TGN was determined using UPLC-MS/MS. Among AIH patients treated with AZA, 40 (35.4%) exhibited different degrees of myelosuppression. The NUDT15 variant was associated with leukopenia (P = 8.26 × 10–7; OR = 7.5; 95% CI 3.08–18.3) and neutropenia (P = 3.54 × 10–6; OR = 8.05; 95% CI 2.96–21.9); however, no significant association with myelosuppression was observed for TPMT3C and ITPA variants (P > 0.05). There was no significant difference in 6-TGN concentration between AIH patients with or without myelosuppression (P = 0.556), nor was there a significant difference between patients with variant alleles of TPMT3C, ITPA, or NUDT15 and wild-type patients (P > 0.05). Interestingly, it was found that patients with a lower BMI had higher adjusted 6-TGN levels and a higher incidence of myelosuppression (P = 0.026 and 0.003). This study confirmed that NUDT15 variants are a potential independent risk predictor for AZA-induced leukopenia and neutropenia. BMI may be a crucial non-genetic factor that affects the concentration of AZA metabolites and myelosuppression. In addition, the 6-TGN concentration in red blood cells does not reflect the toxicity of AZA treatment, and new biomarkers for AZA therapeutic drug monitoring need further research.Qiang MiaoLin YanYanhong ZhouYi LiYuangao ZouLanlan WangYangjuan BaiJunlong ZhangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Qiang Miao Lin Yan Yanhong Zhou Yi Li Yuangao Zou Lanlan Wang Yangjuan Bai Junlong Zhang Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis
description	Abstract This study aimed to investigate the influence of TPMT3C, ITPA, NUDT15, and 6-thioguanine nucleotides (6-TGN) on azathioprine (AZA)-induced myelosuppression in Southwest China patients with autoimmune hepatitis (AIH). A total of 113 Chinese patients with AIH receiving AZA maintenance treatment were evaluated. The relevant clinical data of the patients were collected from the hospital information system. Genotyping of TPMT3C(rs1142345), ITPA (rs1127354) and NUDT15(rs116855232) was conducted using a TaqMan double fluorescent probe. The concentration of 6-TGN was determined using UPLC-MS/MS. Among AIH patients treated with AZA, 40 (35.4%) exhibited different degrees of myelosuppression. The NUDT15 variant was associated with leukopenia (P = 8.26 × 10–7; OR = 7.5; 95% CI 3.08–18.3) and neutropenia (P = 3.54 × 10–6; OR = 8.05; 95% CI 2.96–21.9); however, no significant association with myelosuppression was observed for TPMT3C and ITPA variants (P > 0.05). There was no significant difference in 6-TGN concentration between AIH patients with or without myelosuppression (P = 0.556), nor was there a significant difference between patients with variant alleles of TPMT3C, ITPA, or NUDT15 and wild-type patients (P > 0.05). Interestingly, it was found that patients with a lower BMI had higher adjusted 6-TGN levels and a higher incidence of myelosuppression (P = 0.026 and 0.003). This study confirmed that NUDT15 variants are a potential independent risk predictor for AZA-induced leukopenia and neutropenia. BMI may be a crucial non-genetic factor that affects the concentration of AZA metabolites and myelosuppression. In addition, the 6-TGN concentration in red blood cells does not reflect the toxicity of AZA treatment, and new biomarkers for AZA therapeutic drug monitoring need further research.
format	article
author	Qiang Miao Lin Yan Yanhong Zhou Yi Li Yuangao Zou Lanlan Wang Yangjuan Bai Junlong Zhang
author_facet	Qiang Miao Lin Yan Yanhong Zhou Yi Li Yuangao Zou Lanlan Wang Yangjuan Bai Junlong Zhang
author_sort	Qiang Miao
title	Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis
title_short	Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis
title_full	Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis
title_fullStr	Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis
title_full_unstemmed	Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis
title_sort	association of genetic variants in tpmt, itpa, and nudt15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/afab0be173e54833b6b684fbf1ed459b
work_keys_str_mv	AT qiangmiao associationofgeneticvariantsintpmtitpaandnudt15withazathioprineinducedmyelosuppressioninsouthwestchinapatientswithautoimmunehepatitis AT linyan associationofgeneticvariantsintpmtitpaandnudt15withazathioprineinducedmyelosuppressioninsouthwestchinapatientswithautoimmunehepatitis AT yanhongzhou associationofgeneticvariantsintpmtitpaandnudt15withazathioprineinducedmyelosuppressioninsouthwestchinapatientswithautoimmunehepatitis AT yili associationofgeneticvariantsintpmtitpaandnudt15withazathioprineinducedmyelosuppressioninsouthwestchinapatientswithautoimmunehepatitis AT yuangaozou associationofgeneticvariantsintpmtitpaandnudt15withazathioprineinducedmyelosuppressioninsouthwestchinapatientswithautoimmunehepatitis AT lanlanwang associationofgeneticvariantsintpmtitpaandnudt15withazathioprineinducedmyelosuppressioninsouthwestchinapatientswithautoimmunehepatitis AT yangjuanbai associationofgeneticvariantsintpmtitpaandnudt15withazathioprineinducedmyelosuppressioninsouthwestchinapatientswithautoimmunehepatitis AT junlongzhang associationofgeneticvariantsintpmtitpaandnudt15withazathioprineinducedmyelosuppressioninsouthwestchinapatientswithautoimmunehepatitis
_version_	1718391389698392064

Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis

Ejemplares similares