Observational Study
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World J Gastroenterol. Aug 14, 2014; 20(30): 10591-10598
Published online Aug 14, 2014. doi: 10.3748/wjg.v20.i30.10591
Relationship between methylation and colonic inflammation in inflammatory bowel disease
Triana Lobatón, Daniel Azuara, Francisco Rodríguez-Moranta, Carolina Loayza, Xavier Sanjuan, Javier de Oca, Ana Fernández-Robles, Jordi Guardiola, Gabriel Capellá
Triana Lobatón, Francisco Rodríguez-Moranta, Jordi Guardiola, Department of Gastroenterology, University Hospital of Bellvitge, IDIBELL, Hospitalet de Llobregat, 08907 Barcelona, Spain
Daniel Azuara, Ana Fernández-Robles, Gabriel Capellá, Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, 08907 Barcelona, Spain
Carolina Loayza, Xavier Sanjuan, Department of Pathology, University Hospital of Bellvitge, IDIBELL, Hospitalet de Llobregat, 08907 Barcelona, Spain
Javier de Oca, Department of Surgery, Colorectal Unit, University Hospital of Bellvitge, IDIBELL, Hospitalet de Llobregat, 08907 Barcelona, Spain
Author contributions: Lobatón T was the guarantor of the article; Ortega TL contributed to the study design, data collection, methylation analysis, statistical analysis, interpretation and manuscript writing; Azuara D contributed to the study design, methylation analysis, statistical analysis, interpretation and manuscript writing; Rodríguez-Moranta F contributed to the study design, colonoscopies, statistical analysis, interpretation and manuscript writing; Loayza C and Sanjuan X contributed to the histological analysis; de Oca J contributed to the study design, statistical analysis, interpretation and manuscript writing; Fernández-Robles A contributed to the methylation analysis; Guardiola J contributed to the study design, colonoscopies and sample collection; Capellá G contributed to the study design and manuscript writing.
Supported by Grants from Fondo de Investigación Sanitaria, FIS 12/01420; Ministerio de Ciencia e Innovación, SAF 09-07319, 12-33636; Fundació Gastroenterologia Dr. Francisco Vilardell, F05-01; Ministerio de Educación y Ciencia Spanish Networks RTICC, RD06/0020/0021, 1050 and 1051; RD12/0036/0031 and Fundación Científica de la Asociación Española contra el Cáncer Triana Lobaton supported by a grant from the Institut d’Investigació Biomédica de Bellvitge (IDIBELL)
Correspondence to: Triana Lobatón, MD, Department of Gastroenterology, University Hospital of Bellvitge, IDIBELL, Hospitalet del Llobregat, Gran Via 144, 08907 Barcelona, Spain. tlobaton@bellvitgehospital.cat
Telephone: +34-9-32607623 Fax: +34-9-32607603
Received: January 7, 2014
Revised: March 2, 2014
Accepted: April 21, 2014
Published online: August 14, 2014
Abstract

AIM: To investigate the relationship between the methylation status in the SLIT2 and TGFB2 promoters and colonic inflammation in inflammatory bowel disease patients.

METHODS: We evaluated the methylation status of 2 genes (SLIT2 and TGFB2) in 226 biopsies taken from 62 colonoscopies of 38 patients (29 ulcerative colitis and 9 Crohn’s colitis) using methylation-specific melting curve analysis. The relationships between methylation status and clinical, biological, endoscopic and histological activities were evaluated. Twenty-three of the 38 patients had a second colonoscopy and were included in a longitudinal analysis. Numerical results were given as the means ± SD of the sample and range, except when specified. Student t analysis, U Mann Whitney and ANOVA factor were used to compare the means. Qualitative results were based on the χ2 test.

RESULTS: SLIT2 methylation was more frequent in samples with endoscopic activity than with endoscopic remission (55% vs 18%, P < 0.001). SLIT2 methylation was also higher in samples with acute inflammation (56.5%) than in samples with chronic (24%) or absent inflammation (15%) (P < 0.001). For TGFB2 methylation, the correlation was only significant with endoscopic activity. Methylation was higher in the distal colon for both genes (P < 0.001 for SLIT2 and P = 0.022 for TGFB2). In the multivariate analysis, only inflammation status (and not disease duration or extension) was independently associated with SLIT2 methylation [OR = 6.6 (95%CI: 1.65-27.36), P = 0.009]. In the longitudinal analysis, the maintenance of endoscopic remission was protective for methylation.

CONCLUSION: Endoscopic and histological inflammation are predictive for SLIT2 methylation.

Keywords: Colonic inflammation, Inflammatory bowel disease, Aberrant methylation, Dysplasia, Colitis associated colorectal cancer

Core tip: In this paper, we analyze the relationship between the methylation status of selected genes (TGFB2, SLIT2) and the inflammation status (according to endoscopic and histological activity) in ulcerative colitis and Crohn’s colitis patients with increased risks for colorectal cancer. We observed that methylation correlated better with histological activity than with endoscopic activity. SLIT2 and TGFB2 were more frequently methylated in the distal colon. In the multivariate analysis after adjusting for disease extension, disease duration and inflammatory status, only inflammatory status was an independent predictor of methylation. We also observed that the maintenance of histological healing with time might be protective for methylation.