Influence of MIF polymorphisms on CpG island hyper-methylation of CDKN2A in the patients with ulcerative colitis

Naoko Sakurai; Tomoyuki Shibata; Masakatsu Nakamura; Hikaru Takano; Tasuku Hayashi; Masafumi Ota; Tomoe Nomura-Horita; Ranji Hayashi; Takeo Shimasaki; Toshimi Ostuka; Tomomitsu Tahara; Tomiyasu Arisawa

doi:10.1186/s12881-020-01140-9

Influence of MIF polymorphisms on CpG island hyper-methylation of CDKN2A in the patients with ulcerative colitis

BMC Med Genet. 2020 Oct 12;21(1):201. doi: 10.1186/s12881-020-01140-9.

Affiliations

¹ Department of Gastroenterology, Kanazawa Medical University, 1-1, Daigaku, Uchinada-machi, Ishikawa, 920-0293, Japan.
² Department of Gastroenterology, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan.
³ Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan.
⁴ Department of Gastroenterology, Kanazawa Medical University, 1-1, Daigaku, Uchinada-machi, Ishikawa, 920-0293, Japan. tarisawa@kanazawa-med.ac.jp.

Abstract

Background: 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).

Methods: One hundred and fifty-nine patients diagnosed with UC were enrolled in this study. The methylation status of p14^ARF and p16^INK4a was determined by MSP; MIF genotypes were identified by PCR-SSCP.

Results: 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 p14^ARF or p16^INK4a. Carrying the rs755622 C allele indicated a significantly higher risk for p14^ARF 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 p16^INK4a 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 p14^ARF and p16^INK4a 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).

Conclusions: 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.

Keywords: CDKN2A; CpG hypermethylation; Genetic polymorphism; Macrophage migration inhibitory factor; Ulcerative colitis.

MeSH terms

Adult
Alleles
Colitis, Ulcerative / diagnosis
Colitis, Ulcerative / genetics*
CpG Islands / genetics*
Cyclin-Dependent Kinase Inhibitor p16 / genetics*
DNA Methylation*
Female
Gene Frequency
Genotype
Humans
Intramolecular Oxidoreductases / genetics*
Macrophage Migration-Inhibitory Factors / genetics*
Male
Middle Aged
Polymorphism, Single Nucleotide*
Risk Factors

Substances

CDKN2A protein, human
Cyclin-Dependent Kinase Inhibitor p16
Macrophage Migration-Inhibitory Factors
Intramolecular Oxidoreductases
MIF protein, human