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. 2010 May;115(1):41-50.
doi: 10.1093/toxsci/kfq027. Epub 2010 Jan 27.

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

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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 et al. Toxicol Sci. 2010 May.

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 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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Figures

FIG. 1.
FIG. 1.
Haplotype structure of the XPC gene. A total of 21 unique haplotypes were identified using Bayesian inference implemented in PHASE v2.1.1. A maximum likelihood composite model of phylogenetic analysis in MEGA 4 was conducted on these 21 haplotypes resulting in six PGH (PGH-A, PGH-B, PGH-C, PGH-D, PGH-E, and PGH-F) based on genetic distances, as indicated by the brackets. These six PGHs were used as individual units in further analyses.
FIG. 2.
FIG. 2.
Interaction between PGH-C and smoking, as related to CA frequency. A general linear model adjusted for age and gender was fit to investigate interactions between PGH-C and smoking on CA. A permutation test with 1000 replicates was used to calculate empirical p values to account for multiple testing. Error-bar plots depict mean and 95% confidence interval limits. The round symbols indicate nonsmokers and the triangular symbols indicate smokers. The interaction between smoking and PGH-C was significant (p = 0.046).
FIG. 3.
FIG. 3.
Interaction between PGH-D and PGH-F and smoking as related to mutagen-induced CA frequency. A general linear model adjusted for age and gender was fit to investigate interactions between PGH-D (A) and PGH-F (B) and smoking as related to mutagen-induced CA. A permutation test with 1000 replicates was used to calculate empirical p values, respectively, for each outcome, to account for multiple testing. Error-bar plots depict mean and 95% confidence interval limits. The round symbols indicate nonsmokers and the triangular symbols indicate smokers. The interaction between smoking and PGH-D and PGH-F was significant (p values = 0.023 and 0.031 for PGH-D and PGH-F, respectively).

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