Novel Single Nucleotide Polymorphisms Related to Arsenic-associated Bladder Cancer in a US Population-based Study

Abstract

O-29C8-3 Background/Aims: Arsenic is a carcinogen that contaminates drinking water worldwide. Arsenic concentrations above the current maximum contaminant level (MCL) of 10 micrograms per liter have been detected in over 10% of the unregulated private wells in New Hampshire. Previously, we observed an increased bladder cancer incidence with higher arsenic exposure among smokers in this population. Further, we and others have found evidence that genetic factors influence susceptibility to arsenic-associated malignancies. Methods: We screened a subset of bladder cancer case to identify potential interactions between single nucleotide polymorphisms (SNPs) and elevated arsenic exposure using a panel of 10,000 non-synonymous SNPs. Top hits on the SNP array (Fisher exact test P < 0.0001) were then genotyped in our full case-control study (n = 832 cases, 1119 controls) to determine whether these SNPs were susceptibility loci for arsenic-related bladder cancer. Results: We successfully genotyped SNPs in 2 of the 3 genes identified in the initial scan—one in the FSIP1 gene and another in a solute carrier family member gene. Among ever smokers, the FSIP1 polymorphism was associated with increased bladder cancer incidence (adjusted odds ratio for heterozygotes: 3.40; 95% CI: 1.38, 8.38, and odds ratio for homozygotes for the variant allele 4.61; 95% CI: 1.00, 21.17 compared to homozygotes for the wild type allele) in the high arsenic group and unrelated in the low arsenic group (P for interaction = 0.004). For the solute carrier family polymorphism, the adjusted odds ratios were 3.13; 95% CI: 1.20, 8.19 and 3.96; 95% CI: 1.19, 13.25) for heterozygote and homozygote variants, respectively, and close to one in the low arsenic group (P for interaction = 0.027). Conclusion: In this exploratory analysis, we identified novel SNPs that potentially modify the effects of arsenic on bladder cancer incidence. Further work to understand the functional role of these SNPs is being pursued.