Lifetime water arsenic, genetic susceptibility, and bladder cancer in the New England Bladder Cancer Study

Background Exposure to arsenic in drinking water may interact with common genetic variants in urinary bladder cancer risk. Methods We conducted a gene-environment interaction analysis among 1091 bladder cancer cases and 928 controls from the New England Bladder Cancer Study. Genetic variants tested as effect modifiers included those associated with bladder cancer and arsenic metabolism. Interactions with disease-specific polygenic scores and a genome-wide gene-environment interaction analysis were also conducted. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated with average arsenic concentration (μg/L), average daily arsenic (μg/day), and cumulative arsenic (mg) in water as exposures. Results Multiplicative interactions for bladder cancer risk were identified for cumulative arsenic and rs1046428 of GSTZ1 on 14q23 (TT and TC genotype: OR_T3vsT1 = 1.44, 95% CI = 1.05 to 1.98; P_interaction =. 01) and for average daily arsenic and rs1801133 (C677T) and rs1801131 (A1298C) of MTHFR on 1p36 (TT and TC genotypes: OR_T3vsT1 = 1.53, 95% CI = 1.06 to 2.23; P_interaction =. 02; CC and CA genotype: OR_T3vsT1 = 1.63, 95% CI = 1.16 to 2.29; P_interaction =.01, respectively). A global interaction between arsenic exposure and polygenic scores was also observed (OR_T3vsT1 = 1.80, 95% CI = 1.26 to 2.56; P_interaction =. 01). Genome-wide gene-environment interaction analyses suggested interactions with 5 loci with a P_interaction of no more than 5e-6. Conclusions Genetic variants that function in arsenic metabolism involving folate and oxidative stress pathways and a global summary of genetic susceptibility to bladder cancer may modify the association between elevated arsenic exposure from drinking water and bladder cancer.