Department of Neurology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450014, China.
Department of Neurology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Pudong, Shanghai 201399, China.
Curr Neurovasc Res. 2019;16(2):115-122. doi: 10.2174/1567202616666190412154407.
Paraoxonase (PON) family genes are closely related to the etiology and prognosis of cerebral infarction. This study explored the association of the promoter methylation of PON family genes (PON1, PON2 and PON3) with the risk of cerebral infarction.
In this study, 152 patients with confirmed cerebral infarction were selected as the case group, and 152 healthy controls were selected as the control group. The quantitative methylation-specific PCR (qMSP) was used to determine the promoter methylation levels of PON1, PON2 and PON3 genes. The methylation level was expressed as a methylation reference percentage (PMR).
Our results indicated that PON1 methylation was significantly higher in the case group than in the control group (P = 0.0001). On the contrary, PON3 methylation was significantly lower in the case group than in the control group (P = 0.002). In addition, we found that PON2 gene had a very low level of methylation in both case and control groups (PMR = 0). Subgroup analysis showed that PON1 and PON3 methylation were associated with cerebral infarction only in males (PON1, P = 0.0002; PON3, P = 0.007). Interestingly, the methylation levels of PON1 and PON3 were correlated with each other (case: r = 0.418, P = 0.0001; control: r = 0.3, P = 0.0002). Further multiple regression analysis suggested that elevated methylation levels of PON3 were a protective factor for cerebral infarction [OR (95%CI) = 0.979 (0.96, 0.999), β = -0.021, P = 0.035)], highdensity lipoprotein (HDL) and uric acid (UA) also were protective factors for cerebral infarction [HDL, OR (95% CI) = 0.01 (0.003, 0.033), P < 0.0001); UA, OR (95% CI) = 0.995 (0.991, 0.998), P = 0.003)]. The ROC curve analysis found that the combination of PON3, HDL, and UA had a good predictive power for cerebral infarction (AUC=0.878, 95% CI=0.839-0.918, sensitivity 73.7%, specificity 89.7%, P < 0.0001).
PON1 and PON3 promoter methylation levels in peripheral blood were closely related. PON1 and PON3 methylation were associated with the risk of cerebral infarction in men. PON3 promoter methylation combined with HDL and UA could be used as potential biomarkers for the diagnosis of cerebral infarction.
过氧化物酶（PON）家族基因与脑梗死的病因和预后密切相关。本研究探讨了 PON 家族基因（PON1、PON2 和 PON3）启动子甲基化与脑梗死风险的关系。
本研究选择了 152 例确诊为脑梗死的患者作为病例组，选择了 152 例健康对照作为对照组。采用定量甲基化特异性 PCR（qMSP）测定 PON1、PON2 和 PON3 基因启动子的甲基化水平。甲基化水平表示为甲基化参考百分比（PMR）。
我们的结果表明，病例组的 PON1 甲基化水平明显高于对照组（P=0.0001）。相反，病例组的 PON3 甲基化水平明显低于对照组（P=0.002）。此外，我们发现 PON2 基因在病例组和对照组中的甲基化水平均非常低（PMR=0）。亚组分析表明，PON1 和 PON3 甲基化仅与男性脑梗死相关（PON1，P=0.0002；PON3，P=0.007）。有趣的是，PON1 和 PON3 的甲基化水平相互相关（病例：r=0.418，P=0.0001；对照：r=0.3，P=0.0002）。进一步的多元回归分析表明，PON3 甲基化水平升高是脑梗死的保护因素[比值比（95%置信区间）=0.979（0.96，0.999），β=-0.021，P=0.035]，高密度脂蛋白（HDL）和尿酸（UA）也是脑梗死的保护因素[HDL，比值比（95%置信区间）=0.01（0.003，0.033），P<0.0001）；UA，比值比（95%置信区间）=0.995（0.991，0.998），P=0.003]。ROC 曲线分析发现，PON3、HDL 和 UA 的组合对脑梗死具有良好的预测能力（AUC=0.878，95%CI=0.839-0.918，灵敏度 73.7%，特异性 89.7%，P<0.0001）。
外周血中 PON1 和 PON3 启动子甲基化水平密切相关。PON1 和 PON3 甲基化与男性脑梗死的风险相关。PON3 启动子甲基化与 HDL 和 UA 联合可作为脑梗死诊断的潜在生物标志物。
