血清叶酸与RAR - β、MGMT甲基化在宫颈上皮内瘤变中的交互效应

目的 探讨血清叶酸与RAR - β、MGMT 启动子区CpG岛甲基化在宫颈上皮内瘤变（CIN）中的交互效应。方法 基于课题组建立于山西省（介休市和阳曲县）的已婚妇女人群队列，选取2014年6月 - 9月病理学确诊的CIN患者（CINⅠ147例、CINⅡ/Ⅲ 134例）及正常宫颈妇女（156例）为研究对象。收集全部对象人口学特征及相关因素，采集空腹静脉非抗凝血与宫颈脱落细胞。采用化学发光免疫法检测血清叶酸浓度，甲基化特异性PCR法检测基因CpG岛甲基化状态，导流杂交法判定HPV感染状况。采用Kruskal - Wallis H检验、χ2检验、趋势χ2检验进行资料分析，非条件logistic回归模型和交互作用指标评价交互效应。结果 血清叶酸在NC、CINⅠ和CINⅡ/Ⅲ组总体分布差异有统计学意义（P＜0.001）。低血清叶酸（≤23.13 nmol/L）可增加CINⅠ和CINⅡ/Ⅲ的发生风险（OR = 6.78，95%CI:3.75～12.26；OR = 64.13，95%CI:18.34～224.20），且随病变进展，血清叶酸逐渐降低（χ2趋势 = 92.69，P＜0.001）。CIN组RAR - β、MGMT CpG岛甲基化率均高于NC组，且甲基化率随病变进展逐渐上升（χ2趋势 = 20.19，P＜0.001；χ2趋势 = 15.35，P＜0.001）。在各组中低血清叶酸与RAR - β、 MGMT CpG岛高甲基化均呈正相加交互作用（CINⅠ:S = 2.23，95%CI:1.63～8.08，S = 1.21，95%CI:1.01～10.01；CINⅡ/Ⅲ:S = 2.43，95%CI:1.72～6.80，S = 2.83，95%CI:1.55～8.10），但未显示相乘交互作用（P＞0.05）。结论 低血清叶酸和RAR - β、 MGMT CpG岛高甲基化均可增加CIN的风险，且可能存在相加交互作用。

Interaction between serum folic acid and methylation of RAR-β and MGMT in cervical intraepithelial neoplasia

Objective To explore the interaction between serum folate and promoter regions CpG island methylation of RAR-β and MGMT in cervical intraepithelial neoplasia(CIN). Methods Based on cohort of married women established in Shanxi Province (Jiexiu city and Yangqu county), CIN patients (147 cases of CINⅠ, 134 cases of CINⅡ/Ⅲ) and normal cervical women (156 cases) diagnosed pathologically from June to September 2014 were selected. The demographic characteristics and related factors of all participants were collected, and fasting venous non-anticoagulated blood and cervical exfoliated cells were collected. Serum folate concentration was detected by chemiluminescence immunoassay, methylation specific PCR was used to detect the methylation status of CpG island, and diversion hybridization was used to determine the status of HPV infection. Data were analyzed by Kruskal-Wallis H test, chi-square test and trend of chi-square test. The interaction was evaluated by unconditional logistic regression model and interaction index. Results The overall distribution of serum folate in NC, CINⅠand CINⅡ/Ⅲ was significantly different (P<0.001). Low serum folate (≤23.13nmol/L) increased the risk of CINⅠand CINⅡ/Ⅲ (OR=6.78, 95%CI: 3.75-12.26; OR=64.13, 95%CI:18.34-224.20), and serum folate decreased gradually with the severity of cervical lesions (χ2trend=92.69, P<0.001). The methylation rates of RAR-β and MGMT in CIN groups were higher than those in NC group, and the methylation rate of genes increased gradually with the severity of cervical lesions (χ2trend=20.19, P<0.001; χ2trend=15.35, P<0.001). In CIN groups, low serum folate and hypermethylation of RAR-β and MGMT showed positive interaction (CINⅠ: S=2.23, 95%CI: 1.63-8.08, S=1.21, 95%CI: 1.01-10.01; CINⅡ/Ⅲ: S=2.43, 95%CI:1.72-6.80, S=2.83, 95%CI: 1.55-8.10), but there was no multiplicative interaction (P>0.05). Conclusion Low serum folate and CpG island hypermethylation of RAR-β and MGMT increase the risk of CIN, and there might be additive interaction.