Lifetime Water Arsenic, Genetic Susceptibility, And Bladder Cancer In The New England Bladder Cancer Study

Exposure to arsenic (As) in drinking water may interact with common genetic variants in urinary bladder cancer risk. We conducted a gene-environment interaction (GxE) analysis among 1,091 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 As metabolism. Interactions with disease-specific polygenic scores (PGS) and a genome-wide GxE analysis were also conducted. Odds ratios (OR) with 95% confidence intervals (CI) were estimated with average As concentration (µg/L), average daily As (µg/day), and cumulative As (mg) in water as exposures. Multiplicative interactions for bladder cancer risk were identified for cumulative As and rs1046428 of GSTZ1 on 14q23 (TT/TC genotype: ORT3vsT1 1.44, 95% CI: 1.05 to 1.98, P interaction =0.01), and for average daily As and rs1801133 (C677T) and rs1801131 (A1298C) of MTHFR on 1p36 (TT/TC genotypes: ORT3vsT1 1.53; 95% CI: 1.06 to 2.23, P interaction =0.02; CC/CA genotype: ORT3vsT1 1.63, 95% CI: 1.16 to 2.29, P interaction =0.01, respectively). A global interaction between As exposure and PGS was also observed (ORT3vsT1 1.80; 95% CI: 1.26 to 2.56; P interaction =0.01). Genome-wide GxE analyses suggested interactions with 5 loci with P interaction ≤5e-6. Genetic variants that function in As metabolism involving folate and oxidative stress pathways and a global summary of genetic susceptibility to bladder cancer may modify the association between elevated As exposure from drinking water and bladder cancer.