A comprehensive haplotype analysis of the XPC genomic sequence reveals a cluster of genetic variants associated with sensitivity to tobacco-smoke mutagens.

Toxicological Sciences : an Official Journal of the Society of Toxicology
Catherine M RondelliSherif Z Abdel-Rahman

Abstract

The impact of single-nucleotide polymorphisms (SNPs) of the DNA repair gene XPC on DNA repair capacity (DRC) and genotoxicity has not been comprehensively determined. We constructed a comprehensive haplotype map encompassing all common XPC SNPs and evaluated the effect of Bayesian-inferred haplotypes on DNA damage associated with tobacco smoking, using chromosome aberrations (CA) as a biomarker. We also used the mutagen-sensitivity assay, in which mutagen-induced CA in cultured lymphocytes are determined, to evaluate the haplotype effects on DRC. We hypothesized that if certain XPC haplotypes have functional effects, a correlation between these haplotypes and baseline and/or mutagen-induced CA would exist. Using HapMap and single nucleotide polymorphism (dbSNP) databases, we identified 92 SNPs, of which 35 had minor allele frequencies >or= 0.05. Bayesian inference and subsequent phylogenetic analysis identified 21 unique haplotypes, which segregated into six distinct phylogenetically grouped haplotypes (PGHs A-F). A SNP tagging approach used identified 11 tagSNPs representing these 35 SNPs (r(2) = 0.80). We utilized these tagSNPs to genotype a population of smokers matched to nonsmokers (n = 123). Haplotypes for each individual...Continue Reading

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Citations

Aug 23, 2011·International Archives of Occupational and Environmental Health·Erika HalasovaPavel Vodicka
May 17, 2011·Biochemistry. Biokhimii︠a︡·I R Grin, D O Zharkov
Aug 2, 2014·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Wei WangJun Xu
Jan 10, 2016·Environmental Health and Preventive Medicine·Yoshihiro YoshinoYoshiki Kuroda
May 20, 2015·Nicotine & Tobacco Research : Official Journal of the Society for Research on Nicotine and Tobacco·Zoraida VerdeCatalina Santiago
May 21, 2011·Biomarkers : Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals·Sherif Z Abdel-Rahman, Randa A El-Zein
Dec 13, 2017·Pharmacogenetics and Genomics·Jordan T SpeidelSherif Z Abdel-Rahman

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