Variation in PAH-related DNA adduct levels among non-smokers: The role of multiple genetic polymorphisms and nucleotide excision repair phenotype.

A. Etemadi, F. Islami, D.H. Phillips, R.W.L. Godschalk, A. Golozar, F. Kamangar, A. F. Malekshah, A. Pourshams, S. Elahi, F. Ghojaghi, P. T. Strickland, P. R. Taylor, P. Boffetta, C. C. Abnet, S.M. Dawsey, R. Malekzadeh, F.J. van Schooten

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Polycyclic aromatic hydrocarbons (PAHs) likely play a role in many cancers even in never-smokers. We tried to find a model to explain the relationship between variation in PAH-related DNA adduct levels among people with similar exposures, multiple genetic polymorphisms in genes related to metabolic and repair pathways, and nucleotide excision repair (NER) capacity. In 111 randomly-selected female never-smokers from the Golestan Cohort Study in Iran, we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in 8 DNA repair genes. NER capacity was evaluated by a modified comet assay, and aromatic DNA adduct levels were measured in blood by (32) P-postlabelling. Multivariable regression models were compared by Akaike's information criterion (AIC). Aromatic DNA adduct levels ranged between 1.7 and 18.6 per 10(8) nucleotides (mean: 5.8+3.1). DNA adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non risk-allele genotype, and was higher in the MPO homozygote risk-allele genotype. The sum of risk alleles in these genes significantly correlated with the log-adduct level (r=0.4, p<0.001). Compared with the environmental model, adding phase I SNPs and NER capacity provided the best fit, and could explain 17% more of the variation in adduct levels. NER capacity was affected by polymorphisms in the MTHFR and ERCC1 genes. Female non-smokers in this population had PAH-related DNA adduct levels 3-4 times higher than smokers and occupationally-exposed groups in previous studies, with large inter-individual variation which could best be explained by a combination of phase I genes and NER capacity. (c) 2012 Wiley Periodicals, Inc.
Original languageEnglish
Pages (from-to)2738-2747
Number of pages10
JournalInternational Journal of Cancer
Volume132
Issue number12
DOIs
Publication statusPublished - 15 Jun 2013

Keywords

  • polycyclic aromatic hydrocarbons
  • DNA adducts
  • nucleotide excision repair
  • polymorphism
  • POLYCYCLIC AROMATIC-HYDROCARBONS
  • 1-HYDROXYPYRENE GLUCURONIDE CONCENTRATIONS
  • PULMONARY EPITHELIAL-CELLS
  • GRANDE-DO-SUL
  • ESOPHAGEAL CANCER
  • HEALTHY-SUBJECTS
  • HIGH-RISK
  • EXPOSURE
  • GSTM1
  • LUNG

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