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SLC39A2 and FSIP1 polymorphisms as potential modifiers of arsenic-related bladder cancer

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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.

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Abbreviations

FSIP1:

Fibrous sheath interacting protein 1

SLC39A2:

Solute carrier family 39, member 2

OR:

Odds ratio

CI:

Confidence interval

MCL:

Maximum contaminant level

GST:

Glutathione-S-transferase

μg/g:

Microgram per gram

μg/L:

Microgram per liter

SNP:

Single nucleotide polymorphism

XRCC3:

X-ray repair complementing defective repair in Chinese hamster cells 3

ERCC2:

Excision repair cross-complementing rodent repair deficiency, complementation group 2

VEGF:

Vascular endothelial growth factor

THBS1:

Thrombospondin 1

CCND1:

Cyclin D1

NAT2:

N-acetyltransferase 2

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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.

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Authors and Affiliations

  1. Section of Biostatistics and Epidemiology, Dartmouth Medical School, 1 Medical Center Drive, 7927 Rubin Building, Lebanon, NH, 03756, USA

    Margaret R. Karagas, Angeline S. Andrew, Carmen J. Marsit, Jason H. Moore & Diane Gilbert-Diamond

  2. Division of Epidemiology and Community Health and Masonic Cancer Center, University of Minnesota, West Bank Office Building, 1300 S. Second Street, Suite 300, Minneapolis, MN, 55454-1015, USA

    Heather H. Nelson

  3. Biostatistics Shared Resource, Norris Cotton Cancer Center, Dartmouth Medical School, 1 Medical Center Drive, 7927 Rubin Building, Lebanon, NH, 03756, USA

    Zhongze Li

  4. Department of Biological Sciences, Dartmouth College, 78 N. College St., Hanover, NH, 03755, USA

    Tracy Punshon & Mary-Lou Guerinot

  5. Department of Pathology, Dartmouth Medical School, 1 Medical Center Drive, HB 7900, Lebanon, NH, 03756, USA

    Alan Schned

  6. Department of Pharmacology and Toxicology, Dartmouth Medical School, 7650 Remsen, Hanover, NH, 03755, USA

    Carmen J. Marsit

  7. Research Reactor Center, University of Missouri-Columbia, Columbia, MO, 65211, USA

    J. Steven Morris

  8. Department of Genetics, Dartmouth Medical School, 7400 Remsen Building, Hanover, NH, 03755, USA

    Jason H. Moore, Anna L. Tyler & Diane Gilbert-Diamond

  9. Department of Pathology and Laboratory Medicine, Brown University, Box G-E5, Providence, RI, 02912, USA

    Karl T. Kelsey

  10. Department of Community Health, Brown University, Box G-E5, Providence, RI, 02912, USA

    Karl T. Kelsey

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  1. Margaret R. Karagas
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  2. Angeline S. Andrew
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  3. Heather H. Nelson
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  4. Zhongze Li
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  5. Tracy Punshon
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  6. Alan Schned
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  7. Carmen J. Marsit
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  8. J. Steven Morris
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  9. Jason H. Moore
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  10. Anna L. Tyler
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  11. Diane Gilbert-Diamond
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  12. Mary-Lou Guerinot
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  13. Karl T. Kelsey
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Correspondence to Margaret R. Karagas.

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Karagas, M.R., Andrew, A.S., Nelson, H.H. et al. SLC39A2 and FSIP1 polymorphisms as potential modifiers of arsenic-related bladder cancer. Hum Genet 131, 453–461 (2012). https://doi.org/10.1007/s00439-011-1090-x

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