Interactions between polymorphisms in the 3′untranslated region of the cyclin dependent kinase 6 gene and the human papillomavirus infection and risk of cervical precancerous lesions

摘要

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 χ² 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)adjusted=0.17, 95% confidence interval (CI), 0.05–0.57; AT vs. AA: ORadjusted=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 (ORadjusted=0.21; 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.