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

Catherine M. Rondelli, Randa A. El-Zein, Jeffrey K. Wickliffe, Carol J. Etzel, Sherif Abdel-Rahman

Research output: Contribution to journalArticle

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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 ≥ 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 (r2 = 0.80). We utilized these tagSNPs to genotype a population of smokers matched to nonsmokers (n = 123). Haplotypes for each individual were reconstituted and PGH designations were assigned. Relationships between XPC haplotypes and baseline and/or mutagen-induced CA were then evaluated. We observed significant interaction among smoking and PGH-C (p = 0.046) for baseline CA where baseline CA was 3.5 times higher in smokers compared to nonsmokers. Significant interactions among smoking and PGH-D (p = 0.023) and PGH-F (p = 0.007) for mutagen-induced CA frequencies were also observed. These data indicate that certain XPC haplotypes significantly alter CA and DRC in smokers and, thus, can contribute to cancer risk.

Original languageEnglish (US)
Pages (from-to)41-50
Number of pages10
JournalToxicological Sciences
Volume115
Issue number1
DOIs
StatePublished - May 2010

Fingerprint

Tobacco
Mutagens
Chromosomes
Aberrations
Smoke
Haplotypes
Chromosome Aberrations
Polymorphism
Nucleotides
Single Nucleotide Polymorphism
Repair
DNA Repair
DNA
Smoking
Lymphocytes
HapMap Project
Biomarkers
Assays
Gene Frequency
Genes

Keywords

  • Biomarkers
  • Cancer
  • Chromosome
  • DNA nucleotide excision repair
  • Haplotypes
  • Polymorphism
  • Smoking
  • XPC gene

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

Cite this

A comprehensive haplotype analysis of the XPC genomic sequence reveals a cluster of genetic variants associated with sensitivity to tobacco-smoke mutagens. / Rondelli, Catherine M.; El-Zein, Randa A.; Wickliffe, Jeffrey K.; Etzel, Carol J.; Abdel-Rahman, Sherif.

In: Toxicological Sciences, Vol. 115, No. 1, 05.2010, p. 41-50.

Research output: Contribution to journalArticle

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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 ≥ 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 (r2 = 0.80). We utilized these tagSNPs to genotype a population of smokers matched to nonsmokers (n = 123). Haplotypes for each individual were reconstituted and PGH designations were assigned. Relationships between XPC haplotypes and baseline and/or mutagen-induced CA were then evaluated. We observed significant interaction among smoking and PGH-C (p = 0.046) for baseline CA where baseline CA was 3.5 times higher in smokers compared to nonsmokers. Significant interactions among smoking and PGH-D (p = 0.023) and PGH-F (p = 0.007) for mutagen-induced CA frequencies were also observed. These data indicate that certain XPC haplotypes significantly alter CA and DRC in smokers and, thus, can contribute to cancer risk.",
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