1. ¹Department of Biochemistry & Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
2. ²Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
3. ³Department of Gastroenterology, The Alfred, Melbourne, Victoria, Australia
4. ⁴Gastroenterology Unit, Radcliffe Infirmary, University of Oxford, Oxford, UK
5. ⁵Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
6. ⁶Department of Gastroenterology, University of Bern, Bern, Switzerland
7. ⁷Department of Gastroenterology, Royal Devon and Exeter Hospital, Exeter, UK
8. ⁸These authors contributed equally to this work
9. ⁹Died on 1 January 2007
10. ¹⁰Department of Rheumatology, Clinical Immunology and Allergology, Inselspital, University of Bern, Bern, Switzerland

Correspondence: JS Bond, (jbond@psu.edu); D Lottaz, (daniel.lottaz@insel.ch)

Received 23 July 2008; Accepted 6 January 2009; Published online 4 March 2009.

Abstract

The MEP1A gene, located on human chromosome 6p (mouse chromosome 17) in a susceptibility region for inflammatory bowel disease (IBD), encodes the -subunit of metalloproteinase meprin A, which is expressed in the intestinal epithelium. This study shows a genetic association of MEP1A with IBD in a cohort of ulcerative colitis (UC) patients. There were four single-nucleotide polymorphisms in the coding region (P=0.0012–0.04), and one in the 3'-untranslated region (P=2 10^-7) that displayed associations with UC. Moreover, meprin- mRNA was decreased in inflamed mucosa of IBD patients. Meprin- knockout mice exhibited a more severe intestinal injury and inflammation than their wild-type counterparts following oral administration of dextran sulfate sodium. Collectively, the data implicate MEP1A as a UC susceptibility gene and indicate that decreased meprin- expression is associated with intestinal inflammation in IBD patients and in a mouse experimental model of IBD.