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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.

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.

SUBMITTER: Rondelli CM

PROVIDER: S-EPMC2855352 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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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.

Rondelli Catherine M CM El-Zein Randa A RA Wickliffe Jeffrey K JK Etzel Carol J CJ Abdel-Rahman Sherif Z SZ

Toxicological sciences : an official journal of the Society of Toxicology 20100127 1

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 d ...[more]

PMID: 20106949

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Project description:Maternal smoking has a severe negative effect on all stages of pregnancy that in consequence impairs fetal growth and development. Tobacco smoke-related defects are well established at the clinical level; however, little is known about molecular mechanisms underlying these pathological conditions. We thus employed a genomic approach to determine transcriptome alterations induced by maternal smoking in pregnancy. We assayed gene expression profiles in peripheral blood (M) leukocytes and placentas (PL) of pregnant smokers and those without significant exposure, and in cord blood (D) leukocytes of their babies. Comparative analyses defined significant deregulation of 193 genes in M cells, 329 genes in placentas, and 49 genes in D cells of smokers. These genes were mainly involved in xenobiotic metabolism, oxidative stress, inflammation, immunity, hematopoiesis, trophoblast differentiation, and vascularization. Functional annotation of the deregulated genes outlined processes and pathways affected by tobacco smoke. In smoker newborns, we identified several deregulated pathways associated with autoimmune diseases. The study demonstrates a limited ability of placenta to modulate toxic effects of maternal tobacco use at the gene expression level. Blood and placental samples were obtained from 91 women who gave birth to a baby in the Ceske Budejovice Hospital from November 2008 to March 2009. The study was approved by the Local Institutional Review Board. All participants provided written informed consent and completed an extensive questionnaire on pregnancy history (medication, diseases), delivery course, newborn characteristics and life style (smoking, diet, alcohol drinking, area of residency). Only subjects who underwent vaginal delivery were included in the study. Based on smoking history, the women were divided into two groups, “smokers” (N=20) and “non-smokers” (N=52), while passive smokers (N=19) were excluded from the study. Smoking status was further confirmed by detection of excessive plasma levels of cotinine (the major nicotine metabolite) in maternal blood.

Dataset Information

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

Publications

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

Similar Datasets

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