A case-control study of polymorphisms in xenobiotic and arsenic metabolism genes and arsenic-related bladder cancer in New Hampshire

► We studied genetic modification of arsenic associated bladder cancer risk. ► GSTP1 Ile105Val variant was associated with an increased risk of arsenic-related bladder cancer. ► AQP3 Phe130Phe carriers had a possible increased risk of arsenic-related bladder cancer. ► GSTO2 Asn142Asp and GSTZ1 Glu32Lys were associated with overall bladder cancer risk. Arsenic is associated with bladder cancer risk even at low exposure levels. Genetic variation in enzymes involved in xenobiotic and arsenic metabolism may modulate individual susceptibility to arsenic-related bladder cancer. Through a population-based case-control study in NH (832 cases and 1191 controls), we investigated gene-environment interactions between arsenic metabolic gene polymorphisms and arsenic exposure in relation to bladder cancer risk. Toenail arsenic concentrations were used to classify subjects into low and high exposure groups. Single nucleotide polymorphisms (SNPs) in GSTP1, GSTO2, GSTZ1, AQP3, AS3MT and the deletion status of GSTM1 and GSTT1 were determined. We found evidence of genotype-arsenic interactions in the high exposure group; GSTP1 Ile105Val homozygous individuals had an odds ratio (OR) of 5.4 [95% confidence interval (CI): 1.5–20.2; P for interaction=0.03] and AQP3 Phe130Phe carriers had an OR=2.2 (95% CI: 0.8–6.1; P for interaction=0.10). Bladder cancer risk overall was associated with GSTO2 Asn142Asp (homozygous; OR=1.4; 95% CI: 1.0–1.9; P for trend=0.06) and GSTZ1 Glu32Lys (homozygous; OR=1.3; 95% CI: 0.9–1.8; P for trend=0.06). Our findings suggest that susceptibility to bladder cancer may relate to variation in genes involved in arsenic metabolism and oxidative stress response and potential gene-environment interactions requiring confirmation in other populations.