多环芳烃与p16、FHIT基因CpG岛甲基化在宫颈上皮内瘤变中的交互效应

摘要

目的 探讨多环芳烃与p16、FHIT基因CpG岛甲基化在宫颈上皮内瘤变(CIN)中的作用及其交互效应.方法 利用2014年6--12月建立的山西省阳曲县宫颈病变研究队列.包括经病理学确诊的CIN患者169例(CIN Ⅰ 86例,CINⅡ/Ⅲ83例)和正常宫颈(NC)妇女91例.全部研究对象采用高效液相色谱法检测尿液中的1-羟基芘(1-OHP)浓度,甲基化特异性PCR法检测抑癌基因p16、FHIT CpG岛甲基化状态.应用SPSS 20.0软件进行相关资料的Kruskal-Wallis H检验、x2检验、趋势x2检验,应用logistic回归模型计算因素与宫颈疾病之间关联强度的OR值及其95％CI,应用广义多因子降维模型(GMDR)评价交互作用.结果 随着CIN程度加重,l-OHP水平逐渐上升(H=50.743,P＜0.001),1-OHP高暴露率逐渐升高(趋势检验x2=20.146,P＜0.001).CIN Ⅰ、CINⅡ/Ⅲ组p16、FHIT CpG岛甲基化率均高于NC组;随着C1N程度的加重,p16基因CpG岛甲基化率(趋势检验x2=9.75,P=0.002)、FHIT基因CpG岛甲基化率(趋势检验x2=10.39,P=0.001)均逐渐升高.GMDR交互作用分析显示,在CIN Ⅰ和CINⅡ/Ⅲ组,1-OHP高暴露与p16、FHIT基因CpG岛甲基化呈交互作用.结论 l-OHP高暴露和p16、FHIT CpG岛甲基化均可增加CIN的风险,且在病变中具有协同作用.%Objective To explore the effect ofpolycyclic aromatic hydrocarbons (PAHs) and p16,FHIT gene CpG island methylation,as well as their interaction in cervical intraepithelial neoplasias.Methods Objects of this study were from a cohort of cervical lesions study in Yangqu county of Shanxi province.All the patients were diagnosed pathologically,that including 83 patients with high-grade cervical intraepithelial neoplasia (CIN Ⅱ/Ⅲ),86 patients with low-grade cervical intraepithelial neoplasia (C1N Ⅰ) and another 91 women under normal cervical (NC) condition.1-hydroxy pyrene in the urine was detected by high performance liquid chromatography (HPLC)while CpG island methylation status of tumor suppressor gene p16 and FHIT were measured by methylation-specifc polymerase chain reaction (MSP).Data were analyzed with Kruskal-Wallis H test,chi-square test and trend of chi-square test.Logistic regression models were used to estimate the odds ratio (OR) and corresponding 95％ confidence intervals (95％CI) between influencing factors and the cervical disease by using the SPSS statistical software (version 20.0).The interaction under study was evaluated by using the generalized multifactor dimensionality reduction (GMDR) model.Results Level of 1-hydroxy pyrene (H=50.743,P＜0.001) and the high exposure rate of 1-hydroxy pyrene (trend x2=20.146,P＜0.001) were gradually increasing along with the severity of cervical intraepithelial neoplasia.The CpG island methylation rates ofpl6,FHIT in CIN] and CIN Ⅱ/Ⅲl group were higher than that in NC group,and gradually increasing along with the severity of cervical intraepithelial neoplasia (trend x2=9.75,P=0.002;trend x 2 =10.39,P=0.001).Results from the GMDR model showed that interaction existed among the high exposure of l-hydroxy pyrene and the CpG island methylation ofpl6,FHIT in CIN Ⅰ and CIN Ⅱ]/Ⅲ group.Conclusion Under the high exposure of 1-hydroxy pyrene and the CpG island methylation of p16,FHIT appeared to have increased the risk of cervical intraepithelial neoplasia and causing synergistic effect in cervical intraepithelial neoplasia.