title: Genetic variation in glutathione S-transferase omega-1, arsenic methyltransferase and methylene-tetrahydrofolate reductase, arsenic exposure and bladder cancer: a case-control study.
abstract: BACKGROUND
  Ingestion of groundwater with high concentrations of inorganic arsenic has been linked to adverse health outcomes, including bladder cancer, however studies have not consistently observed any elevation in risk at lower concentrations. Genetic variability in the metabolism and clearance of arsenic is an important consideration in any investigation of its potential health risks. Therefore, we examined the association between genes thought to play a role in the metabolism of arsenic and bladder cancer.
  
  
  METHODS
  Single nucleotide polymorphisms (SNPs) in GSTO-1, As3MT and MTHFR were genotyped using DNA from 219 bladder cancer cases and 273 controls participating in a case-control study in Southeastern Michigan and exposed to low to moderate (<50 μg/L) levels of arsenic in their drinking water. A time-weighted measure of arsenic exposure was constructed using measures from household water samples combined with past residential history, geocoded and merged with archived arsenic data predicted from multiple resources.
  
  
  RESULTS
  While no single SNP in As3MT was significantly associated with bladder cancer overall, several SNPs were associated with bladder cancer among those exposed to higher arsenic levels. Individuals with one or more copies of the C allele in rs11191439 (the Met287Thr polymorphism) had an elevated risk of bladder cancer (OR = 1.17; 95% CI = 1.04-1.32 per 1 μg/L increase in average exposure). However, no association was observed between average arsenic exposure and bladder cancer among TT homozygotes in the same SNP. Bladder cancer cases were also 60% less likely to be homozygotes for the A allele in rs1476413 in MTHFR compared to controls (OR = 0.40; 95% CI = 0.18-0.88).
  
  
  CONCLUSIONS
  Variation in As3MT and MTHFR is associated with bladder cancer among those exposed to relatively low concentrations of inorganic arsenic. Further investigation is warranted to confirm these findings.
authors: Program of Population Studies and Disparities Research, Karmanos Cancer Institute, 4100 John R, Detroit, MI 48201, USA. dimmerj@karmanos.org
authors: Jennifer L
authors: JL
authors: Beebe-Dimmer
authors: Priyanka T
authors: PT
authors: Iyer
authors: Jerome O
authors: JO
authors: Nriagu
authors: Greg R
authors: GR
authors: Keele
authors: Shilpin
authors: S
authors: Mehta
authors: Jaymie R
authors: JR
authors: Meliker
authors: Ethan M
authors: EM
authors: Lange
authors: Ann G
authors: AG
authors: Schwartz
authors: Kimberly A
authors: KA
authors: Zuhlke
authors: David
authors: D
authors: Schottenfeld
authors: Kathleen A
authors: KA
authors: Cooney
mesh_terms: D000368:Aged; D001151:Arsenic / Q000378:metabolism / Q000633:toxicity*; D016022:Case-Control Studies; D060766:Drinking Water / Q000032:analysis; D004781:Environmental Exposure; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008780:Methyltransferases / Q000235:genetics*; D008824:Michigan / Q000453:epidemiology; D008875:Middle Aged; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D001749:Urinary Bladder Neoplasms / Q000453:epidemiology / Q000235:genetics*
chemical_list: D060766:Drinking Water; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008780:Methyltransferases; C505756:AS3MT protein, human; C490476:GSTO1 protein, human; D005982:Glutathione Transferase; D001151:Arsenic