Lo Yen-Li, Jou Yuh-Shan, Hsiao Chin-Fu, Chang Gee-Chen, Tsai Ying-Huang, Su Wu-Chou, Chen Kuan-Yu, Chen Yuh-Min, Huang Ming-Shyan, Hu Chi Yuan, Chen Chien-Jen, Hsiung Chao A
Division of Biostatistics and Bioinformatics, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan.
Cancer Epidemiol Biomarkers Prev. 2009 Jan;18(1):223-9. doi: 10.1158/1055-9965.EPI-08-0749.
Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential enzyme in the base excision repair pathway, which is the primary mechanism for the repair of DNA damage caused by oxidation and alkylation. We hypothesized that polymorphisms of APE1 are associated with risk for lung cancer. In the hospital-based matched case-control study, a total of 730 lung cancer cases and 730 cancer-free controls were genotyped for four APE1 haplotype-tagging polymorphisms (that is, -656T>G, 400A>G, 630T>C, and 1350T>G). Among them, the single-nucleotide polymorphism -656T>G located in the promoter region of APE1 was significantly associated with risk for lung cancer. We found that, compared with -656 TT homozygotes, the variant genotypes were associated with a significantly decreased risk [adjusted odds ratio, 0.51; 95% confidence interval (95% CI), 0.33-0.79 for -656 TG; adjusted odds ratio, 0.43; 95% CI, 0.25-0.76 for -656 GG, respectively]. Furthermore, we found a statistically significant reduced risk of -656T>G variants among heavy smokers (adjusted odds ratio, 0.52; 95% CI, 0.30-0.93 for -656 TG; adjusted odds ratio, 0.27; 95% CI, 0.13-0.57 for -656 GG, respectively), with a significant gene-smoking interaction (P = 0.013). A similar gene-smoking interaction in the context of APE1 haplotypes was also observed. The in vitro promoter assay revealed that the -656 G allele had a significantly higher transcriptional activity than that of the -656 T allele. Together, our results suggest that polymorphisms of the APE1 gene possibly interact with smoking and may contribute to the development of lung cancer.
脱嘌呤/脱嘧啶内切酶1（APE1）是碱基切除修复途径中的一种关键酶，该途径是修复由氧化和烷基化导致的DNA损伤的主要机制。我们推测APE1的多态性与肺癌风险相关。在这项基于医院的匹配病例对照研究中，对730例肺癌病例和730例无癌对照进行了4种APE1单倍型标签多态性（即-656T>G、400A>G、630T>C和1350T>G）的基因分型。其中，位于APE1启动子区域的单核苷酸多态性-656T>G与肺癌风险显著相关。我们发现，与-656 TT纯合子相比，变异基因型与风险显著降低相关[-656 TG的调整优势比为0.51；95%置信区间（95%CI）为0.33 - 0.79；-656 GG的调整优势比为0.43；95%CI为0.25 - 0.76]。此外，我们发现重度吸烟者中-656T>G变异的风险在统计学上显著降低[-656 TG的调整优势比为0.52；95%CI为0.30 - 0.93；-656 GG的调整优势比为0.27；95%CI为0.13 - 0.57]，且存在显著的基因-吸烟相互作用（P = 0.013）。在APE1单倍型背景下也观察到了类似的基因-吸烟相互作用。体外启动子分析显示，-656 G等位基因的转录活性显著高于-656 T等位基因。总之，我们的结果表明，APE1基因的多态性可能与吸烟相互作用，并可能促成肺癌的发生。
