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

Journal of Biomedical Science

Research

Ya-Tang Liao¹  Meei-Maan Wu²  Wann-Cheng Lo²  Ling-I Hsu²  Tse-Yen Yang²  Wu-Ping Chen²  Yu-Hsin Chen²  Chien-Jen Chen²  Hung-Yi Chiou³  Yu-Mei Hsueh³  Yuan-Hung Wang⁴ 

[1] Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Taiwan;Genomics Research Center, Academia Sinica, No.128 Academia road, Sec 2, 115, Nankang, Taipei, Taiwan;School of Public Health, Taipei Medical University, 250 Wu-Xin Street, 110, Taipei, Taiwan;School of Public Health, Taipei Medical University, 250 Wu-Xin Street, 110, Taipei, Taiwan;Department of Urology, Taipei Medical University Hospital, 250 Wu-Xin Street, 110, Taipei, Taiwan;

关键词: Arsenic;    Urothelial Carcinoma;    Arsenic Exposure;    Increase Cancer Risk;    GSTT1 Null Genotype;   

DOI  :  10.1186/1423-0127-18-51

 received in 2011-03-03, accepted in 2011-07-29,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundArsenic 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.MethodsTo 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.ResultsThe 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.ConclusionsThe 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.

【 授权许可】

Unknown   
© Hsu et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.