Brief Article
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World J Gastroenterol. Aug 14, 2013; 19(30): 4935-4943
Published online Aug 14, 2013. doi: 10.3748/wjg.v19.i30.4935
Analysis of single nucleotide polymorphisms in the region of CLDN2-MORC4 in relation to inflammatory bowel disease
Jan Söderman, Elisabeth Norén, Malin Christiansson, Hanna Bragde, Raphaele Thiébaut, Jean-Pierre Hugot, Curt Tysk, Colm A O’Morain, Miquel Gassull, Yigael Finkel, Jean-Frédéric Colombel, Marc Lémann, Sven Almer
Jan Söderman, Elisabeth Norén, Malin Christiansson, Hanna Bragde, Division of Medical Diagnostics, Ryhov County Hospital, 55185 Jönköping, Sweden
Elisabeth Norén, Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden
Raphaele Thiébaut, Jean-Pierre Hugot, INSERM, U843, Université Paris Diderot, Hôpital Robert Debré, 75019 Paris, France
Raphaele Thiébaut, Jean-Pierre Hugot, Université Paris-Diderot Sorbonne Paris-Cité, UMR843, 75018 Paris, France
Jean-Pierre Hugot, Assistance Publique-Hopitaux de Paris, Hopital Robert Debré, 75019 Paris, France
Curt Tysk, Division of Gastroenterology, Department of Medicine, University Hospital, School of Health and Medical Sciences, Örebro University, 70185 Örebro, Sweden
Curt Tysk, School of Health and Medical Sciences, Örebro University, 70185 Örebro, Sweden
Colm A O’Morain, Department of Gastroenterology, Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland
Colm A O’Morain, Trinity College Dublin, College Green, Dublin 2, Ireland
Miquel Gassull, Health Sciences Research Institute, Germans Trias i Pujol, 08916 Badalona, Spain
Yigael Finkel, Department of Gastroenterology, Sachs’ Children’s Hospital, Södersjukhuset, 11861 Stockholm, Sweden
Jean-Frédéric Colombel, EPIMAD group, Registre EPIMAD, Service d’Epidémiologie et de Santé Publique, Hôpital Calmette, Centre Hospitalier Universitaire de Lille, 59037 Lille, France
Jean-Frédéric Colombel, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Marc Lémann, GETAID group, Groupe d’Etude Thérapeutiques des Affections Inflammatoires Digestives, Service de gastroentérologie, Hôpital Saint Louis, 75010 Paris, France
Sven Almer, Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden
Sven Almer, Department of Gastroenterology UHL, County Council of Östergötland, 58185 Linköping, Sweden
Sven Almer, Division of Gastroenterology, Karolinska Institutet, Department of Gastroenterology and Hepatology, Karolinska university hospital, 14186 Stockholm, Sweden
Author contributions: Söderman J and Norén E contributed equally to this work; Söderman J and Almer S conceived of the study; Söderman J, Norén E and Almer S designed the study, contributed to data analysis and interpretation, and drafted the manuscript; Söderman J, Norén E, Christiansson M and Bragde H contributed to genotyping and sequencing; Hugot JP, Tysk C, O’Morain CA, Gassull M, Finkel Y, Colombel JF, Lémann M (deceased) and Almer S provided blood samples and patient data; Söderman J, Norén E and Thiébaut R performed the statistical analysis; Hugot JP participated in study design and coordination; all authors read and approved the final manuscript.
Supported by Grants from Futurum - the academy of healthcare, County council of Jönköping; the Swedish Society of Medicine; the Research Council of South-East Sweden (FORSS) and the County Council of Östergötland (ALF-Grants)
Correspondence to: Elisabeth Norén, BSc, Division of Medical Diagnostics, Ryhov County Hospital, Sjukhusgatan, 55185 Jönköping, Sweden. elisabeth.noren@lj.se
Telephone: +46-36-322302 Fax: +46-36-180073
Received: December 23, 2012
Revised: April 24, 2013
Accepted: June 5, 2013
Published online: August 14, 2013
Processing time: 235 Days and 19.7 Hours
Abstract

AIM: To investigate a possible genetic influence of claudin (CLDN)1, CLDN2 and CLDN4 in the etiology of inflammatory bowel disease.

METHODS: Allelic association between genetic regions of CLDN1, CLDN2 or CLDN4 and patients with inflammatory bowel disease, Crohn’s disease (CD) or ulcerative colitis were investigated using both a case-control study approach (one case randomly selected from each of 191 Swedish inflammatory bowel disease families and 333 controls) and a family-based study (463 non-Swedish European inflammatory bowel disease -families). A nonsynonymous coding single nucleotide polymorphism in MORC4, located on the same linkage block as CLDN2, was investigated for association, as were two novel CLDN2 single nucleotide polymorphism markers, identified by resequencing.

RESULTS: A single nucleotide polymorphism marker (rs12014762) located in the genetic region of CLDN2 was significantly associated to CD (case-control allelic OR = 1.98, 95%CI: 1.17-3.35, P = 0.007). MORC4 was present on the same linkage block as this CD marker. Using the case-control approach, a significant association (case control allelic OR = 1.61, 95%CI: 1.08-2.41, P = 0.018) was found between CD and a nonsynonymous coding single nucleotide polymorphism (rs6622126) in MORC4. The association between the CLDN2 marker and CD was not replicated in the family-based study. Ulcerative colitis was not associated to any of the single nucleotide polymorphism markers.

CONCLUSION: These findings suggest that a variant of the CLDN2-MORC4 region predisposes to CD in a Swedish population.

Keywords: Crohn’s disease; Genetic predisposition; Inflammatory bowel disease; Single nucleotide polymorphism; Tight junctions

Core tip: Tight junction proteins are key components in the regulation of paracellular permeability and therefore we considered claudin genes as candidate genes in the study. Association was identified between a single nucleotide polymorphism marker (rs12014762) in the CLDN2-MORC4 region and the occurrence of Crohn’s disease (CD) in a Swedish population. Additionally, a nonsynonymous coding single nucleotide polymorphism (rs6622126) in MORC4 was associated to CD. Our findings add further support for a genetically impaired intestinal epithelial barrier as one predisposing factor in the etiology of CD.