title: Variation in PAH-related DNA adduct levels among non-smokers: the role of multiple genetic polymorphisms and nucleotide excision repair phenotype.
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 eight DNA repair genes. NER capacity was evaluated by a modified comet assay, and aromatic DNA adduct levels were measured in blood by32P-postlabeling. 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 three to four 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.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20852, USA. arash.etemadi@nih.gov
authors.forename: Arash
authors.initials: A
authors.lastname: Etemadi
authors.forename: Farhad
authors.initials: F
authors.lastname: Islami
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.forename: Roger
authors.initials: R
authors.lastname: Godschalk
authors.forename: Asieh
authors.initials: A
authors.lastname: Golozar
authors.forename: Farin
authors.initials: F
authors.lastname: Kamangar
authors.forename: Akbar Fazel-Tabar
authors.initials: AF
authors.lastname: Malekshah
authors.forename: Akram
authors.initials: A
authors.lastname: Pourshams
authors.forename: Seerat
authors.initials: S
authors.lastname: Elahi
authors.forename: Farhad
authors.initials: F
authors.lastname: Ghojaghi
authors.forename: Paul T
authors.initials: PT
authors.lastname: Strickland
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.forename: Christian C
authors.initials: CC
authors.lastname: Abnet
authors.forename: Sanford M
authors.initials: SM
authors.lastname: Dawsey
authors.forename: Reza
authors.initials: R
authors.lastname: Malekzadeh
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: van Schooten
mesh_terms: D000328:Adult; D000483:Alleles; D015331:Cohort Studies; D018736:DNA Adducts; D004260:DNA Repair; D005260:Female; D005838:Genotype; D006801:Humans; D007492:Iran; D008875:Middle Aged; D010641:Phenotype; D011084:Polycyclic Aromatic Hydrocarbons; D020641:Polymorphism, Single Nucleotide
chemical_list: D018736:DNA Adducts; D011084:Polycyclic Aromatic Hydrocarbons; C095911:polycyclic aromatic hydrocarbons-DNA adduct