Arsenic is a carcinogen that contaminates drinking water worldwide. Accumulating evidence suggests that both exposure and genetic factors may influence susceptibility to arsenic-induced malignancies. We sought to identify novel susceptibility loci for arsenic-related bladder cancer in a US population with low to moderate drinking water levels of arsenic.We first screened a subset of bladder cancer cases using a panel of approximately 10,000 nonsynonymous single nucleotide polymorphisms (SNPs). Top ranking hits on the SNP array then were considered for further analysis in our population-based case-control study (n = 832 cases and 1,191 controls). SNPs in the fibrous sheath interacting protein 1 (FSIP1) gene (rs10152640) and the solute carrier family 39, member 2 (SLC39A2) in the ZIP gene family of metal transporters (rs2234636) were detected as potential hits in the initial scan and validated in the full case-control study. The adjusted odds ratio (OR) for the FSIP1 polymorphism was 2.57 [95% confidence interval (CI) 1.13, 5.85] for heterozygote variants (AG) and 12.20 (95% CI 2.51, 59.30) for homozygote variants (GG) compared to homozygote wild types (AA) in the high arsenic group (greater than the 90th percentile), and unrelated in the low arsenic group (equal to or below the 90th percentile) (P for interaction = 0.002). For the SLC39A2 polymorphism, the adjusted ORs were 2.96 (95% CI 1.23, 7.15) and 2.91 (95% CI 1.00, 8.52) for heterozygote (TC) and homozygote (CC) variants compared to homozygote wild types (TT), respectively, and close to one in the low arsenic group (P for interaction = 0.03). Our findings suggest novel variants that may influence risk of arsenicassociated bladder cancer and those who may be at greatest risk from this widespread exposure.
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Acknowledgments We thank the physicians, pathology laboratories, staff members and many participants of the New Hampshire Health Study for making this study possible. This publication was funded in part by grant numbers 5 P42 ES007373 and P20 ES018175 from the National Institute of Environmental Health Sciences, NIH and R01 CA57494 and K07 CA102327 from the National Cancer Institute, NIH and R01 LM009012 from the National Library of Medicine, NIH and RD-83459901 from the EPA. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NCI, NIH and EPA.