Abstract
BackgroundIngestion 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.MethodsSingle 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.ResultsWhile 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).ConclusionsVariation 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.
Highlights
Ingestion of groundwater with high concentrations of inorganic arsenic has been linked to adverse health outcomes, including bladder cancer, studies have not consistently observed any elevation in risk at lower concentrations
The data to support these relationships were first gathered from investigations in areas of chronic and endemic arseniasis, in the past decade there has been an increasing amount of attention devoted to study of the health consequences of low to moderate concentrations of arsenic consumed from contaminated household drinking water (
While our study is the first to report an interaction between Arsenic (+3) Methyltransferase (As3MT) (10q24.32) and arsenic exposure on bladder cancer risk, these findings are consistent with evidence gleaned from several other studies demonstrating that polymorphisms in As3MT are involved in the methylation of inorganic arsenic [24,25,26,27,28,29,33,44]
Summary
Ingestion of groundwater with high concentrations of inorganic arsenic has been linked to adverse health outcomes, including bladder cancer, studies have not consistently observed any elevation in risk at lower concentrations. Our findings from a population-based case–control study conducted in Southeastern Michigan are in agreement with other U.S studies indicating no significant association overall between arsenic exposure from drinking water and bladder cancer risk [10]. Results have not been uniformly negative, as studies in Northeastern Taiwan, Chile and others in Argentina have reported increases in bladder cancer risk and mortality associated with arsenic concentrations as low as 10-50 μg/L depending upon the length of exposure [11,12,13,14,15]
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