Association between polymorphisms in the XRCC1 and GST genes, and CpG island methylation status in colonic mucosa in ulcerative colitis

Tahara, Tomomitsu; Shibata, Tomoyuki; Nakamura, Masakatsu; Okubo, Masaaki; Yamashita, Hiromi; Yoshioka, Daisuke; Yonemura, Joh; Hirata, Ichiro; Arisawa, Tomiyasu

doi:10.1007/s00428-010-1038-x

Cited by 11 publications

(8 citation statements)

References 35 publications

(49 reference statements)

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“…CIHM has been reported within non-neoplastic colonic mucosal tissues of patients diagnosed with UC; likewise, chronic in ammation has been shown to promote age-related methylation [19]. Our previously study also revealed aberrant methylation of the tumor suppressors p14 ARF and p16 INK4a , both encoded by Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) locus, in the non-neoplastic colonic mucosal tissues of patients with UC [20].…”

Section: Introductionsupporting

confidence: 58%

Influence of MIF Polymorphisms on CpG Island Hyper-methylation of CDKN2A in the Patients With Ulcerative Colitis

Sakurai¹,

Shibata

Nakamura³

et al. 2020

Preprint

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Background: CDKN2A hypermethylation is among of 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 p14ARF and p16INK4a was determined by MSP; MIF genotypes were identified by PCR-SSCP. Results: The frequencies of the rs755662 GC + CC genotype and rs5844572 7-repeat allele were significantly higher in group with methylated p14ARF and methylated p16INK4a, respectively. 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); similarly, carrying the rs5844572 7-repeat allele indicated a significantly higher risk for p16INK4a methylation (OR, 2.57; 95% CI, 1.26–5.24) after an adjusted regression analysis. The carriers of the rs755662 C allele and 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 and OR, 2.87; 95% CI, 1.25–6.62, respectively). Conclusions: Taken together, our findings suggest that MIF genotypes associated with inflammation may also be involved in promoting carcinogenesis via CDKN2A hyper-methylation in patients diagnosed with UC.

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Section: Introductionsupporting

confidence: 58%

Influence of MIF Polymorphisms on CpG Island Hyper-methylation of CDKN2A in the Patients With Ulcerative Colitis

Sakurai¹,

Shibata

Nakamura³

et al. 2020

Preprint

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“…Recently, Tahara, one of the co-authors in this study, revealed a high rate of hypermethylation in the severe phenotype of UC, particularly at the CpG islands, by genome-wide methylation analysis, and that these methylated genes were related to those involved in biosynthetic processes, the regulation of metabolic processes, and nitrogen compound metabolic processes [42]. In addition, we have already reported that function gain genotypes of various immune-or in ammation-related molecules were associated with an increased CpG methylation of CDH1, encoding e-cadherin, and CDKN2A [43,44]. Further studies for an association of various genotypes with CpG islands methylation of the responsible genes for development of CAC will be needed.…”

Section: Discussionmentioning

confidence: 93%

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

Sakurai¹,

Shibata

Nakamura³

et al. 2020

Preprint

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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 p14ARF and p16INK4a 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 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).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.

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“…Each score was based on the endoscopic findings, as follows: 0, normal or inactive disease; 1, mild disease (erythema, decreased vascular pattern, and mild friability); 2, moderate disease (marked erythema, absent vascular pattern, friability, and erosions); and 3, severe disease (spontaneous bleeding and ulcerations). This cohort was recruited from our study investigating the association between promoter DNA methylation and clinical phenotypes, [22] host genetic factors [23] and telomere length [24] .…”

Section: Methodsmentioning

confidence: 99%

DNA Methylation Status of Epithelial-Mesenchymal Transition (EMT) - Related Genes Is Associated with Severe Clinical Phenotypes in Ulcerative Colitis (UC)

et al. 2014

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BackgroundEpithelial-to-mesenchymal transition (EMT) is a phenomenon that allows the conversion of adherent epithelial cells to a mesenchymal cell phenotype, which enhances migratory capacity and invasiveness. Recent studies have suggested that EMT contributes to the pathogenesis of ulcerative colitis (UC). We investigated the promoter DNA methylation status of EMT-related genes in the colonic mucosa in UC.MethodsColonic biopsies were obtained from the rectal inflammatory mucosa of 86 UC patients and the non-inflammatory proximal colonic mucosa of 10 paired patients. Bisulfite pyrosequencing was used to quantify the methylation of 5 candidate CpG island promoters (NEUROG1, CDX1, miR-1247, CDH1, and CDH13) and LINE1.ResultsUsing an unsupervised hierarchical clustering analysis, inflamed rectal mucosa was well separated from mucosa that appeared normal. The CDH1 and CDH13 promoters were significantly associated with patient age (p = 0.04, 0.03, respectively). A similar trend was found between those genes and the duration of disease (CDH1: p = 0.07, CDH13: p = 0.0002, mean of both: p<0.00001). Several positive associations were found between hypermethylation and severe clinical phenotypes (CDX1 and miR-1247 and a refractory phenotype: p = 0.04 and 0.006, respectively. miR-1247 and CDH1 hyper methylation and a more severe Mayo endoscopic subscore: miR-1247: p = 0.0008, CDH1: p = 0.03, mean of both: p = 0.003). When the severe clinical phenotype was defined as having any of five phenotypes (hospitalized more than twice, highest Mayo endoscopic subscore, steroid dependence, refractory, or a history of surgery) miR-1247 hypermethylation was associated with the same phenotype (p = 0.008).ConclusionsOur data suggest that variability in the methylation status of EMT-related genes is associated with more severe clinical phenotypes in UC.

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Association between polymorphisms in the XRCC1 and GST genes, and CpG island methylation status in colonic mucosa in ulcerative colitis

Cited by 11 publications

References 35 publications

Influence of MIF Polymorphisms on CpG Island Hyper-methylation of CDKN2A in the Patients With Ulcerative Colitis

Influence of MIF Polymorphisms on CpG Island Hyper-methylation of CDKN2A in the Patients With Ulcerative Colitis

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

DNA Methylation Status of Epithelial-Mesenchymal Transition (EMT) - Related Genes Is Associated with Severe Clinical Phenotypes in Ulcerative Colitis (UC)

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