title: SLC39A2 and FSIP1 polymorphisms as potential modifiers of arsenic-related bladder cancer.
abstract: 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 non-synonymous 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 arsenic-associated bladder cancer and those who may be at greatest risk from this widespread exposure.
authors.affiliation: Section of Biostatistics and Epidemiology, Dartmouth Medical School, Lebanon, NH 03756, USA. Margaret.r.karagas@dartmouth.edu
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Karagas
authors.forename: Angeline S
authors.initials: AS
authors.lastname: Andrew
authors.forename: Heather H
authors.initials: HH
authors.lastname: Nelson
authors.forename: Zhongze
authors.initials: Z
authors.lastname: Li
authors.forename: Tracy
authors.initials: T
authors.lastname: Punshon
authors.forename: Alan
authors.initials: A
authors.lastname: Schned
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.forename: J Steven
authors.initials: JS
authors.lastname: Morris
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.forename: Anna L
authors.initials: AL
authors.lastname: Tyler
authors.forename: Diane
authors.initials: D
authors.lastname: Gilbert-Diamond
authors.forename: Mary-Lou
authors.initials: ML
authors.lastname: Guerinot
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
mesh_terms: D000368:Aged; D001151:Arsenic / Q000633:toxicity*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics*; D060766:Drinking Water; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009513:New Hampshire; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D029589:Seminal Plasma Proteins / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D014877:Water Pollution, Chemical; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D060766:Drinking Water; C552592:FSIP1 protein, human; C498424:SLC39A2 protein, human; D029589:Seminal Plasma Proteins; D001151:Arsenic