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Genetic variation in Glutathione S-Transferase Omega-1, Arsenic Methyltransferase and Methylene-tetrahydrofolate Reductase, arsenic exposure and bladder cancer: a case–control study

Jennifer L Beebe-Dimmer12*, Priyanka T Iyer1, Jerome O Nriagu3, Greg R Keele12, Shilpin Mehta2, Jaymie R Meliker4, Ethan M Lange56, Ann G Schwartz12, Kimberly A Zuhlke7, David Schottenfeld8 and Kathleen A Cooney79

Author Affiliations

1 Program of Population Studies and Disparities Research, Karmanos Cancer Institute, 4100 John R, Detroit, MI 48201, USA

2 Department of Oncology, Wayne State University, Detroit, MI, USA

3 Department of Environmental Health Sciences and Epidemiology, University of Michigan, Ann Arbor, MI, USA

4 Department of Preventive Medicine and Graduate Program in Public Health, StonyBrook University Medical Center, New York, Stony Brook, USA

5 Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

6 Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA

7 Department of Internal Medicine, University of Michigan Medical School Ann Arbor, Ann Arbor, MI, USA

8 Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA

9 Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA

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Environmental Health 2012, 11:43  doi:10.1186/1476-069X-11-43

Published: 29 June 2012



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.


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.


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).


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.

Genetic epidemiology; Single nucleotide polymorphisms; Urothelial cancer; Arsenic methylation