Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston, Texas 77555 1062, USA.
Toxicol Sci. 2010 May;115(1):41-50. doi: 10.1093/toxsci/kfq027. Epub 2010 Jan 27.
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.
XPC 基因的单核苷酸多态性（SNP）对 DNA 修复能力（DRC）和遗传毒性的影响尚未得到全面确定。我们构建了一个全面的单倍型图谱，涵盖了所有常见的 XPC SNP，并使用染色体畸变（CA）作为生物标志物，评估了贝叶斯推断的单倍型对与吸烟相关的 DNA 损伤的影响。我们还使用了诱变敏感性测定法，该方法测定了培养的淋巴细胞中诱变剂诱导的 CA，以评估单倍型对 DRC 的影响。我们假设如果某些 XPC 单倍型具有功能影响，那么这些单倍型与基线和/或诱变剂诱导的 CA 之间就存在相关性。使用 HapMap 和单核苷酸多态性（dbSNP）数据库，我们确定了 92 个 SNP，其中 35 个 SNP 的次要等位基因频率≥0.05。贝叶斯推断和随后的系统发育分析确定了 21 个独特的单倍型，这些单倍型分为六个不同的系统发育分组的单倍型（PGH A-F）。一个 SNP 标记方法用于鉴定了 11 个代表这些 35 个 SNP 的标记 SNP（r²=0.80）。我们利用这些标记 SNP 对与非吸烟者相匹配的吸烟者群体进行了基因分型（n=123）。对每个个体的单倍型进行了重建，并指定了 PGH 名称。然后评估了 XPC 单倍型与基线和/或诱变剂诱导的 CA 之间的关系。我们观察到吸烟与 PGH-C（p=0.046）之间存在显著的交互作用，基线 CA 吸烟人群中基线 CA 是非吸烟者的 3.5 倍。还观察到吸烟与 PGH-D（p=0.023）和 PGH-F（p=0.007）之间的显著交互作用，这些交互作用与诱变剂诱导的 CA 频率有关。这些数据表明，某些 XPC 单倍型显著改变了吸烟者的 CA 和 DRC，从而可以增加患癌症的风险。
