Genetic polymorphisms in glutathione S-transferase (GST) superfamily and risk of arsenic-induced urothelial carcinoma in residents of southwestern Taiwan

Ling I. Hsu, Wu Ping Chen, Tse Yen Yang, Yu Hsin Chen, Wann Cheng Lo, Yuan Hung Wang, Ya Tang Liao, Yu Mei Hsueh, Hung Yi Chiou, Meei Maan Wu, Chien Jen Chen

研究成果: 雜誌貢獻文章

24 引文 (Scopus)

摘要

Background: Arsenic exposure is an important public health issue worldwide. Dose-response relationship between arsenic exposure and risk of urothelial carcinoma (UC) is consistently observed. Inorganic arsenic is methylated to form the metabolites monomethylarsonic acid and dimethylarsinic acid while ingested. Variations in capacity of xenobiotic detoxification and arsenic methylation might explain individual variation in susceptibility to arsenic-induced cancers. Methods. To estimate individual susceptibility to arsenic-induced UC, 764 DNA specimens from our long-term follow-up cohort in Southwestern Taiwan were used and the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and arsenic methylation enzymes including GSTO1 and GSTO2 were genotyped. Results: The GSTT1 null was marginally associated with increased urothelial carcinoma (UC) risk (HR, 1.91, 95% CI, 1.00-3.65), while the association was not observed for other GSTs. Among the subjects with cumulative arsenic exposure (CAE) 20 mg/L*year, the GSTT1 null genotype conferred a significantly increased cancer risk (RR, 3.25, 95% CI, 1.20-8.80). The gene-environment interaction between the GSTT1 and high arsenic exposure with respect to cancer risk was statistically significant (multiplicative model, p = 0.0151) and etiologic fraction was as high as 0.86 (95% CI, 0.51-1.22). The genetic effects of GSTO1/GSTO2 were largely confined to high arsenic level (CAE 20). Diplotype analysis showed that among subjects exposed to high levels of arsenic, the AGG/AGG variant of GSTO1 Ala140Asp, GSTO2 5'UTR (-183)A/G, and GSTO2 Asn142Asp was associated with an increased cancer risk (HRs, 4.91, 95% CI, 1.02-23.74) when compared to the all-wildtype reference, respectively. Conclusions: The GSTs do not play a critical role in arsenic-induced urothelial carcinogenesis. The genetic effects of GSTT1 and GSTO1 on arsenic-induced urothelial carcinogenesis are largely confined to very high exposure level.

原文英語
文章編號51
期刊Journal of Biomedical Science
18
發行號1
DOIs
出版狀態已發佈 - 2011

指紋

Arsenic
Genetic Polymorphisms
Glutathione Transferase
Polymorphism
Taiwan
Carcinoma
Methylation
Neoplasms
Carcinogenesis
Cacodylic Acid
Gene-Environment Interaction
Detoxification
5' Untranslated Regions
Public health
Xenobiotics
Metabolites
Public Health
Genes

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Molecular Biology
  • Cell Biology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism
  • Pharmacology (medical)

引用此文

Genetic polymorphisms in glutathione S-transferase (GST) superfamily and risk of arsenic-induced urothelial carcinoma in residents of southwestern Taiwan. / Hsu, Ling I.; Chen, Wu Ping; Yang, Tse Yen; Chen, Yu Hsin; Lo, Wann Cheng; Wang, Yuan Hung; Liao, Ya Tang; Hsueh, Yu Mei; Chiou, Hung Yi; Wu, Meei Maan; Chen, Chien Jen.

於: Journal of Biomedical Science, 卷 18, 編號 1, 51, 2011.

研究成果: 雜誌貢獻文章

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title = "Genetic polymorphisms in glutathione S-transferase (GST) superfamily and risk of arsenic-induced urothelial carcinoma in residents of southwestern Taiwan",
abstract = "Background: Arsenic exposure is an important public health issue worldwide. Dose-response relationship between arsenic exposure and risk of urothelial carcinoma (UC) is consistently observed. Inorganic arsenic is methylated to form the metabolites monomethylarsonic acid and dimethylarsinic acid while ingested. Variations in capacity of xenobiotic detoxification and arsenic methylation might explain individual variation in susceptibility to arsenic-induced cancers. Methods. To estimate individual susceptibility to arsenic-induced UC, 764 DNA specimens from our long-term follow-up cohort in Southwestern Taiwan were used and the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and arsenic methylation enzymes including GSTO1 and GSTO2 were genotyped. Results: The GSTT1 null was marginally associated with increased urothelial carcinoma (UC) risk (HR, 1.91, 95{\%} CI, 1.00-3.65), while the association was not observed for other GSTs. Among the subjects with cumulative arsenic exposure (CAE) 20 mg/L*year, the GSTT1 null genotype conferred a significantly increased cancer risk (RR, 3.25, 95{\%} CI, 1.20-8.80). The gene-environment interaction between the GSTT1 and high arsenic exposure with respect to cancer risk was statistically significant (multiplicative model, p = 0.0151) and etiologic fraction was as high as 0.86 (95{\%} CI, 0.51-1.22). The genetic effects of GSTO1/GSTO2 were largely confined to high arsenic level (CAE 20). Diplotype analysis showed that among subjects exposed to high levels of arsenic, the AGG/AGG variant of GSTO1 Ala140Asp, GSTO2 5'UTR (-183)A/G, and GSTO2 Asn142Asp was associated with an increased cancer risk (HRs, 4.91, 95{\%} CI, 1.02-23.74) when compared to the all-wildtype reference, respectively. Conclusions: The GSTs do not play a critical role in arsenic-induced urothelial carcinogenesis. The genetic effects of GSTT1 and GSTO1 on arsenic-induced urothelial carcinogenesis are largely confined to very high exposure level.",
author = "Hsu, {Ling I.} and Chen, {Wu Ping} and Yang, {Tse Yen} and Chen, {Yu Hsin} and Lo, {Wann Cheng} and Wang, {Yuan Hung} and Liao, {Ya Tang} and Hsueh, {Yu Mei} and Chiou, {Hung Yi} and Wu, {Meei Maan} and Chen, {Chien Jen}",
year = "2011",
doi = "10.1186/1423-0127-18-51",
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TY - JOUR

T1 - Genetic polymorphisms in glutathione S-transferase (GST) superfamily and risk of arsenic-induced urothelial carcinoma in residents of southwestern Taiwan

AU - Hsu, Ling I.

AU - Chen, Wu Ping

AU - Yang, Tse Yen

AU - Chen, Yu Hsin

AU - Lo, Wann Cheng

AU - Wang, Yuan Hung

AU - Liao, Ya Tang

AU - Hsueh, Yu Mei

AU - Chiou, Hung Yi

AU - Wu, Meei Maan

AU - Chen, Chien Jen

PY - 2011

Y1 - 2011

N2 - Background: Arsenic exposure is an important public health issue worldwide. Dose-response relationship between arsenic exposure and risk of urothelial carcinoma (UC) is consistently observed. Inorganic arsenic is methylated to form the metabolites monomethylarsonic acid and dimethylarsinic acid while ingested. Variations in capacity of xenobiotic detoxification and arsenic methylation might explain individual variation in susceptibility to arsenic-induced cancers. Methods. To estimate individual susceptibility to arsenic-induced UC, 764 DNA specimens from our long-term follow-up cohort in Southwestern Taiwan were used and the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and arsenic methylation enzymes including GSTO1 and GSTO2 were genotyped. Results: The GSTT1 null was marginally associated with increased urothelial carcinoma (UC) risk (HR, 1.91, 95% CI, 1.00-3.65), while the association was not observed for other GSTs. Among the subjects with cumulative arsenic exposure (CAE) 20 mg/L*year, the GSTT1 null genotype conferred a significantly increased cancer risk (RR, 3.25, 95% CI, 1.20-8.80). The gene-environment interaction between the GSTT1 and high arsenic exposure with respect to cancer risk was statistically significant (multiplicative model, p = 0.0151) and etiologic fraction was as high as 0.86 (95% CI, 0.51-1.22). The genetic effects of GSTO1/GSTO2 were largely confined to high arsenic level (CAE 20). Diplotype analysis showed that among subjects exposed to high levels of arsenic, the AGG/AGG variant of GSTO1 Ala140Asp, GSTO2 5'UTR (-183)A/G, and GSTO2 Asn142Asp was associated with an increased cancer risk (HRs, 4.91, 95% CI, 1.02-23.74) when compared to the all-wildtype reference, respectively. Conclusions: The GSTs do not play a critical role in arsenic-induced urothelial carcinogenesis. The genetic effects of GSTT1 and GSTO1 on arsenic-induced urothelial carcinogenesis are largely confined to very high exposure level.

AB - Background: Arsenic exposure is an important public health issue worldwide. Dose-response relationship between arsenic exposure and risk of urothelial carcinoma (UC) is consistently observed. Inorganic arsenic is methylated to form the metabolites monomethylarsonic acid and dimethylarsinic acid while ingested. Variations in capacity of xenobiotic detoxification and arsenic methylation might explain individual variation in susceptibility to arsenic-induced cancers. Methods. To estimate individual susceptibility to arsenic-induced UC, 764 DNA specimens from our long-term follow-up cohort in Southwestern Taiwan were used and the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and arsenic methylation enzymes including GSTO1 and GSTO2 were genotyped. Results: The GSTT1 null was marginally associated with increased urothelial carcinoma (UC) risk (HR, 1.91, 95% CI, 1.00-3.65), while the association was not observed for other GSTs. Among the subjects with cumulative arsenic exposure (CAE) 20 mg/L*year, the GSTT1 null genotype conferred a significantly increased cancer risk (RR, 3.25, 95% CI, 1.20-8.80). The gene-environment interaction between the GSTT1 and high arsenic exposure with respect to cancer risk was statistically significant (multiplicative model, p = 0.0151) and etiologic fraction was as high as 0.86 (95% CI, 0.51-1.22). The genetic effects of GSTO1/GSTO2 were largely confined to high arsenic level (CAE 20). Diplotype analysis showed that among subjects exposed to high levels of arsenic, the AGG/AGG variant of GSTO1 Ala140Asp, GSTO2 5'UTR (-183)A/G, and GSTO2 Asn142Asp was associated with an increased cancer risk (HRs, 4.91, 95% CI, 1.02-23.74) when compared to the all-wildtype reference, respectively. Conclusions: The GSTs do not play a critical role in arsenic-induced urothelial carcinogenesis. The genetic effects of GSTT1 and GSTO1 on arsenic-induced urothelial carcinogenesis are largely confined to very high exposure level.

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