CDKN2A hypermethylation is among the major events associated with carcinogenesis and is also observed in non-neoplastic colonic mucosa in patients with ulcerative colitis (UC). Macrophage migration inhibitory factor (MIF) plays a crucial role in promoting gastrointestinal inflammation characteristic of UC. The aim of this study is to explore associations between CDKN2A methylation status and MIF polymorphisms (rs755622 and rs5844572). One hundred and fifty-nine patients diagnosed with UC were enrolled in this study. The methylation status of p14ARF and p16INK4a was determined by MSP; MIF genotypes were identified by PCR-SSCP. We found no differences with respect to mean age, gender, clinical type (chronic continuous or relapse/remitting), or extent of disease among the patients with methylated and unmethylated p14ARF or p16INK4a. Carrying the rs755622 C allele indicated a significantly higher risk for p14ARF methylation (odds ratio (OR), 2.16; 95% confidence interval (CI), 1.08–4.32; p = 0.030); similarly, carrying the rs5844572 7-repeat allele indicated a significantly higher risk for p16INK4a methylation (OR, 2.57; 95% CI, 1.26–5.24; p = 0.0094) after an adjusted regression analysis. The carriers of the rs755662 C allele or the rs5844572 7-repeat allele were both at a significantly higher risk for methylation of both p14ARF and p16INK4a when compared to the cohort in which neither of the genes were methylated (OR, 2.70; 95% CI, 1.22–6.01; p = 0.015 and OR, 2.87; 95% CI, 1.25–6.62; p = 0.013, respectively). Additionally, carrying rs755622 C allele was significantly associated with CIHM in chronic continuous of clinical type and total colitis (OR, 25.9; 95% CI, 2.55–262.6; p = 0.0059 and OR, 4.38; 95% CI, 1.12–17.2; p = 0.034, respectively), and carrying 7-repeat allele of rs5844572 was significantly associated in chronic continuous type (OR, 14.5; 95%CI, 1.46–144.3; p = 0.022). Taken together, our findings suggest that MIF genotypes associated with inflammation may also be involved in promoting carcinogenesis via CDKN2A hypermethylation in patients diagnosed with UC.

中文翻译：

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影响MIF上的CpG岛超甲基化多态性CDKN2A在溃疡性结肠炎患者

CDKN2A甲基化过高是与致癌作用相关的主要事件之一，在溃疡性结肠炎（UC）患者的非肿瘤性结肠粘膜中也观察到了CDKN2A甲基化过高。巨噬细胞迁移抑制因子（MIF）在促进UC胃肠道炎症特征中起着关键作用。这项研究的目的是探索CDKN2A甲基化状态与MIF多态性（rs755622和rs5844572）之间的关联。159名诊断为UC的患者参加了这项研究。用MSP测定p14ARF和p16INK4a的甲基化状态。通过PCR-SSCP鉴定MIF基因型。我们发现，在甲基化和未甲基化的p14ARF或p16INK4a患者中，平均年龄，性别，临床类型（慢性连续或复发/复发）或疾病程度没有差异。携带rs755622 C等位基因表明p14ARF甲基化的风险显着更高（几率（OR）为2.16； 95％置信区间（CI）为1.08-4.32； p = 0.030）。类似地，经过校正回归分析后，携带rs5844572 7重复等位基因表明p16INK4a甲基化的风险显着较高（OR为2.57； 95％CI为1.26-5.24； p = 0.0094）。与其中一个基因均未甲基化的队列相比，rs755662 C等位基因或rs5844572 7重复等位基因的携带者均处于较高的p14ARF和p16INK4a甲基化风险（OR为2.70； 95％CI， 1.22–6.01； p = 0.015； OR = 2.87； 95％CI：1.25–6.62； p = 0.013）。另外，在临床类型和全结肠炎的慢性连续发作中，携带rs755622 C等位基因与CIHM显着相关（OR，25.9； 95％CI，2.55-262.6；p = 0.0059，OR = 4.38；95％CI，1.12-17.2；p = 0.034）和携带rs5844572的7重复等位基因在慢性连续型中显着相关（OR为14.5； 95％CI为1.46–144.3； p = 0.022）。综上所述，我们的发现表明，与炎症相关的MIF基因型也可能通过CDKN2A甲基化在诊断为UC的患者中促进癌变。