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.
authors.affiliation: Genomics Research Center, Academia Sinica, No.128 Academia road, Sec 2, Nankang, Taipei 115, Taiwan.
authors.forename: Ling-I
authors.initials: LI
authors.lastname: Hsu
authors.forename: Wu-Ping
authors.initials: WP
authors.lastname: Chen
authors.forename: Tse-Yen
authors.initials: TY
authors.lastname: Yang
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Chen
authors.forename: Wann-Cheng
authors.initials: WC
authors.lastname: Lo
authors.forename: Yuan-Hung
authors.initials: YH
authors.lastname: Wang
authors.forename: Ya-Tang
authors.initials: YT
authors.lastname: Liao
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Hsueh
authors.forename: Hung-Yi
authors.initials: HY
authors.lastname: Chiou
authors.forename: Meei-Maan
authors.initials: MM
authors.lastname: Wu
authors.forename: Chien-Jen
authors.initials: CJ
authors.lastname: Chen
mesh_terms: D001151:Arsenic / Q000633:toxicity*; D017931:DNA Primers / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D013624:Taiwan; D014571:Urologic Neoplasms / Q000139:chemically induced* / Q000235:genetics*
chemical_list: D017931:DNA Primers; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase; D001151:Arsenic