Intestinal inflammation

Associations with tight junction genes PARD3 and MAGI2 in Dutch patients point to a common barrier defect for coeliac disease and ulcerative colitisAn unusual case of ascites

M C Wapenaar^1,2, A J Monsuur¹, A A van Bodegraven³, R K Weersma⁴, M R Bevova¹, R K Linskens⁵, P Howdle⁶, G Holmes⁷, C J Mulder³, G Dijkstra⁴, D A van Heel⁸, C Wijmenga^1,2

¹ Complex Genetics Section, DBG-Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
² Genetics Department, University Medical Center Groningen, Groningen, The Netherlands
³ Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
⁴ Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
⁵ Department of Gastroenterology and Internal Medicine, St Anna Ziekenhuis, Geldrop, The Netherlands
⁶ St James University Hospital, Leeds, UK
⁷ Derby Royal Infirmary, Derby, UK
⁸ Institute of Cell and Molecular Science, Barts and The London, Queen Mary’s School of Medicine and Dentistry, London, UK

Dr M C Wapenaar, Genetics Department, Room E2.030, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands; m.c.wapenaar{at}medgen.umcg.nl

Background: Coeliac disease (gluten-sensitive enteropathy; GSE) and inflammatory bowel disease (IBD) are common gastrointestinal disorders. Both display enhanced intestinal permeability, initiated by gluten exposure (GSE) or bacterial interactions (IBD). Previous studies showed the association of both diseases with variants in MYO9B, presumably involved in epithelial permeability.

Aim: It was hypothesised that genetic variants in tight junction genes might affect epithelial barrier function, thus contributing to a shared pathogenesis of GSE and IBD.

Methods: This hypothesis was tested with a comprehensive genetic association analysis of 41 genes from the tight junction pathway, represented by 197 tag single nucleotide polymorphism (SNP) markers.

Results: Two genes, PARD3 (two SNPs) and MAGI2 (two SNPs), showed weak association with GSE in a Dutch cohort. Replication in a British GSE cohort yielded significance for one SNP in PARD3 and suggestive associations for two additional SNPs, one each in PARD3 and MAGI2. Joint analysis of the British and Dutch data further substantiated the association for both PARD3 (rs10763976, p = 6.4x10^–5; OR 1.23, 95% CI 1.11 to 1.37) and MAGI2 (rs6962966, p = 7.6x10^–4; OR 1.19, 95% CI 1.08 to 1.32). Association was also observed in Dutch ulcerative colitis patients with MAGI2 (rs6962966, p = 0.0036; OR 1.26, 95% CI 1.08 to 1.47), and suggestive association with PARD3 (rs4379776, p = 0.068).

Conclusions: These results suggest that coeliac disease and ulcerative colitis may share a common aetiology through tight junction-mediated barrier defects, although the observations need further replication.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Article

The significance of the gut barrier in disease

Jon Meddings
Gut 2008 57: 438-440. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Tripathi, A., Lammers, K. M., Goldblum, S., Shea-Donohue, T., Netzel-Arnett, S., Buzza, M. S., Antalis, T. M., Vogel, S. N., Zhao, A., Yang, S., Arrietta, M.-C., Meddings, J. B., Fasano, A. (2009). Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc. Natl. Acad. Sci. USA 106: 16799-16804 [Abstract] [Full Text]  
• Muise, A M, Walters, T D, Glowacka, W K, Griffiths, A M, Ngan, B-Y, Lan, H, Xu, W, Silverberg, M S, Rotin, D (2009). Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn's disease. Gut 58: 1121-1127 [Abstract] [Full Text]  
• Festen, E A M, Goyette, P, Scott, R, Annese, V, Zhernakova, A, Lian, J, Lefebvre, C, Brant, S R, Cho, J H, Silverberg, M S, Taylor, K D, de Jong, D J, Stokkers, P C, Mcgovern, D, Palmieri, O, Achkar, J-P, Xavier, R J, Daly, M J, Duerr, R H, Wijmenga, C, Weersma, R K, Rioux, J D (2009). Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis. Gut 58: 799-804 [Abstract] [Full Text]  
• Spiller, R. (2008). The year in Gut 2008. Gut 57: 1637-1638 [Full Text]  
• Meddings, J. (2008). The significance of the gut barrier in disease. Gut 57: 438-440 [Full Text]