Ye Xingguang, Jing Lipeng, Zhong Xingming, Xiao Di, Ou Meiling, Guo Congcong, Yang Guang, Jing Chunxia, Wei Xiangcai
Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China.
Family Planning Research Institute of Guangdong, Guangzhou, Guangdong 510062, P.R. China.
Biomed Rep. 2017 Jun;6(6):640-648. doi: 10.3892/br.2017.898. Epub 2017 May 3.
The human papillomavirus (HPV) infection is essential for the development of cervical cancer and its precursor lesions. However, only certain persistently infected individuals develop cervical cancer. Cyclin-dependent kinase 6 (CDK6) is a critical regulatory cancer-associated gene in the cell cycle and in tumorigenesis. Single nucleotide polymorphisms (SNPs) in microRNA sites in the 3'-untranslated region (UTR) of target genes may result in target gene expression level changes and susceptibility to diseases, including cancer. Therefore, the aim of the present study was to determine whether SNPs in the 3'UTR of the CDK6 gene may affect susceptibility to cervical precancerous lesions in a Chinese population. Five polymorphisms in the 3'UTR of the CDK6 gene were evaluated in 164 cervical precancerous lesion cases and 296 control subjects. Differences in environmental factors between cases and controls were evaluated using the χ test or unpaired t-test. Logistic regression was used to examine the association between the five polymorphisms and cervical precancerous lesions. The model-free multifactor dimensionality reduction (MDR) method was performed to evaluate the interaction effect of environment variables and gene polymorphisms. Interactions on the additive scale are calculated by using the relative excess risk due to interaction (RERI). After controlling for potential confounders, a significantly decreased risk of cervical precancerous lesions for the GA genotype, rs8179, and the AT genotype, rs42033 [GA vs. GA: odds ratio (OR)=0.17, 95% confidence interval (CI), 0.05-0.57; AT vs. AA: OR=0.18, 95% CI, 0.05-0.59, respectively] was identified. Furthermore, following MDR analysis, a significant three-locus interaction model was identified, which involved the HPV infection, the number of pregnancies and rs8179. Additionally, a significant antagonistic interaction between the HPV infection and rs8179 was identified on an additive scale. Haplotype AGTA was associated with a decreased risk of developing cervical precancerous lesions (OR0.21; 95% CI, 0.06-0.75). Thus, the present results indicated that the rs8179 and rs42033 polymorphisms confer genetic susceptibility to cervical precancerous lesions. Furthermore, the interaction between the rs8179 polymorphism in CDK6 and the HPV infection and haplotype AGTA may be associated with cervical precancerous lesions.
人乳头瘤病毒（HPV）感染是宫颈癌及其癌前病变发生发展的必要条件。然而，只有某些持续感染的个体才会患上宫颈癌。细胞周期蛋白依赖性激酶6（CDK6）是细胞周期和肿瘤发生过程中关键的调控性癌症相关基因。靶基因3'非翻译区（UTR）中微小RNA位点的单核苷酸多态性（SNP）可能导致靶基因表达水平改变以及对包括癌症在内的疾病的易感性。因此，本研究旨在确定CDK6基因3'UTR中的SNP是否可能影响中国人群对宫颈上皮内瘤变的易感性。在164例宫颈上皮内瘤变病例和296例对照受试者中评估了CDK6基因3'UTR中的5种多态性。采用χ检验或非配对t检验评估病例组和对照组之间环境因素的差异。采用逻辑回归分析5种多态性与宫颈上皮内瘤变之间的关联。采用无模型多因素降维（MDR）方法评估环境变量与基因多态性的交互作用。采用交互作用相对超额危险度（RERI）计算相加尺度上的交互作用。在控制潜在混杂因素后，发现rs8179的GA基因型和rs42033的AT基因型使宫颈上皮内瘤变风险显著降低[GA与GG比较：比值比（OR）=0.17，95%置信区间（CI），0.05 - 0.57；AT与AA比较：OR = 0.18，95% CI，0.05 - 0.59]。此外，MDR分析后，确定了一个显著的三位点交互作用模型，该模型涉及HPV感染、妊娠次数和rs8179。此外，在相加尺度上确定了HPV感染与rs8179之间存在显著的拮抗交互作用。单倍型AGTA与宫颈上皮内瘤变发生风险降低相关（OR0.21；95% CI，0.06 - 0.75）。因此，本研究结果表明，rs8179和rs42033多态性赋予了宫颈上皮内瘤变的遗传易感性。此外，CDK6基因中rs8179多态性与HPV感染及单倍型AGTA之间的交互作用可能与宫颈上皮内瘤变有关。
