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Gene-environment interactions between DNA repair polymorphisms and exposure to the carcinogen vinyl chloride.

Authors
Li-Y; Marion-MJ; Zipprich-J; Santella-RM; Freyer-G; Brandt-Rauf-PW
Source
Biomarkers 2009 May; 14(3):148-155
NIOSHTIC No.
20035443
Abstract
We have recently suggested that polymorphisms in metabolism and repair pathways may play a role in modulating the effects of exposure to the carcinogen vinyl chloride in the production of biomarkers of its mutagenic damage. The aim of the present study was to extend these observations by examining gene-environment interactions between several common polymorphisms in the DNA repair genes XRCC1 and ERCC2/XPD and vinyl chloride exposure on the production of vinyl chloride-induced biomarkers of mutation. A cohort of 546 French vinyl chloride workers were genotyped for the XRCC1 codon 194 (Arg>Trp; rs1799782), 280 (Arg>His; rs25489) and 399 (Arg>Gln; rs25487) polymorphisms and the ERCC2/XPD codon 312 (Asp>Asn; rs1799793) and 751 (Lys>Gln; rs13181) polymorphisms. The results demonstrated a statistically significant allele dosage effect of the XRCC1 399 variant on the production of the vinyl chloride-induced mutant p53 biomarker, even after controlling for confounders including cumulative vinyl chloride exposure (p = 0.03), with a potentially supramultiplicative gene-environment interaction. In addition, the results demonstrate statistically significant allele dosage effects of the ERCC2/XPD 312 and 751 variants on the production of the vinyl chloride-induced mutant ras-p21 biomarker, even after controlling for confounders including cumulative vinyl chloride exposure (p < 0.0001 and p = 0.0006, respectively), with a potentially supramultiplicative gene-environment interaction for the codon 751 allele. Finally, the results suggest potential supramultiplicative gene-gene interactions between CYP2E1 (c2 allele; rs3813867) and ERCC2/XPD polymorphisms that are consistent with the proposed carcinogenic pathway for vinyl chloride, which requires metabolic activation by CYP2E1 to reactive intermediates that form DNA adducts that, if not removed by DNA repair mechanisms, result in oncogenic mutations.
Keywords
Biomarkers; Cancer; Cell-metabolism; Cell-morphology; Cellular-reactions; DNA-damage; Dose-response; Exposure-assessment; Gene-mutation; Genes; Genetic-disorders; Genetic-factors; Genetics; Genotoxic-effects; Genotoxicity; Humans; Mutation; Oncogenic-agents; Oncogenicity Statistical-analysis; Author Keywords: Gene-environment interaction; polymorphisms; mutations; biomarkers; cancer
Contact
Paul Brandt-Rauf, Office of the Dean, School of Public Health, University of Illinois at Chicago, 1603 West Taylor Street, Room 1145, Chicago, IL 60612
CODEN
BIOMFA
CAS No.
75-01-4
Publication Date
20090501
Document Type
Journal Article
Email Address
pwb1@uic.edu
Funding Amount
163500
Funding Type
Grant
Fiscal Year
2009
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-004192
Issue of Publication
3
ISSN
1354-750X
Source Name
Biomarkers
State
NY; IL
Performing Organization
Department of Environmental Health Sciences, The Mailman School of Public Health, Columbia University, New York, New York
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