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P706 Metallothioneins are downregulated in ileal mucosa of familial diarrhea syndrome patients susceptible to Crohn's disease.

R.R. Tronstad*1, 2, H.-R. Brattbakk1, C. Stansberg1, K. Hanevik1, K.D.-C. Pham3, E. Ellinghaus4, K. Ersland1, H.L. von Volkmann5, S.F. Jørgensen6, 7, O.H. Gilja8, 9, N. Hovdenak3, T. Hausken3, 5, M.H. Vatn10, 11, A. Franke4, P.M. Knappskog1, 12, T.H. Karlsen7, 13, 14, S. Le Hellard15, 16, 17, T. Fiskerstrand1, 18

1University of Bergen, Department of Clinical Science, Bergen, Norway, 2Haukeland University Hospital, Department of Pediatrics, Bergen, Norway, 3Haukeland University Hospital, Department of Medicine, Bergen, Norway, 4Christian Albrechts University of Kiel, Institute of Clinical Molecular Biology, Kiel, Germany, 5University of Bergen, Department of Clinical Medicine, Bergen, Norway, 6Oslo University Hospital Rikshospitalet, Research Institute of Internal Medicine Department of Transplantation Medicine,, Division of Cancer medicine,Surgery and Transplantation, Oslo, Norway, 7University of Oslo, K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, Oslo, Norway, 8University of Bergen, Deartment of Clinical Medicine, Bergen, Norway, 9Haukeland University Hospital, National Centre for Ultrasound in Gastroenterology,Department of Medicine, Bergen, Norway, 10University of Oslo, Department of Clinical Molecular Biology and Laboratory Sciences (EpiGen), Division of Medicine, Akershus University Hospital, Oslo, Norway, 11Oslo University Hospital, Rikshospitalet, Medical Clinic, Oslo, Norway, 12Haukeland University Hospital, Centre for Medical Genetics and Molecular Medicine, Bergen, Norway, 13Oslo University Hospital Rikshospitalet, Research Institute of Internal Medicine Department of Transplantation Medicine,, Division of Cancer medicine,Surgery and Transplantation, Oslo, Norway, 14Oslo University Hospital, Rikshospitalet, Norwegian PSC Research Center, Department of Transplantation Medicine,, Division of Cancer medicine,Surgery and Transplantation, Oslo, Norway, 15University of Bergen, K. G. Jebsen Centre for Psychosis Research,Department of Clinical Science, Bergen, Norway, 16Haukeland University Hospital, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine , Bergen, Norway, 17University of Bergen, NORMENT,Department of Clinical Science , Bergen, Norway, 18Haukeland University Hospital, Centre for Medical Genetics and Molecular Medicine, Bergen , Norway

Background

Familial GUCY2C diarrhea syndrome (FGDS) is a rare dominantly inherited disease first described in a large Norwegian family (n=34). It is caused by an activating mutation in the gene encoding guanylate cyclase C [1] , the intestinal receptor for heat stable E.coli toxin, guanylins and the new drug linaclotide. Patients with FGDS have early onset chronic mild diarrhea and symptoms resembling IBS, but also increased susceptibility to ileal Crohn's disease (CD) (7 patients) and distal small bowel obstruction (9 patients). The aim of the present study was to compare global gene expression in ileal biopsies from FGDS patients, unrelated CD patients and healthy controls. In addition, we assessed whether CD genetic risk variants [2] segregate with ileitis in the FGDS patients.

Methods

Global gene expression was examined in ileal biopsies from 11 FGDS patients, (3 with CD), 6 unrelated CD patients, and 16 healthy controls (age 22-57), using Illumina Human HT-12 v4 Expression Bead Chip. Histology of the biopsy site was normal in all but one FGDS patient.

We genotyped 140 CD risk variants [2] using the Immunochip (Illumina Infinium) array and sequenced the NOD2 gene in 23 FGDS-patients above 30 years of age (7 with CD). A polygenic risk-score was calculated for each subject.

Results

A moderate number of genes were differentially expressed between FGDS patients and healthy controls. Of special interest were nine metallothioneins (MT1A, MT1E, MT1F, MT1G, MT1H, MT1M, MT1X, MT2A and MTE), which were 1.5-3 fold downregulated in FGDS patients. Gene ontology analyses showed significant enrichment for metallothionein-related terms. There were no significant differences in expression of metallothioneins in the unrelated CD patients compared to controls.

The polygenic risk score did not differ between FGDS patients with and without CD, and none of the 140 CD risk variants segregated perfectly with CD in this family. However, 6 of the 7 FGDS patients with CD carried NOD2 risk variants (JW1, R702W, R703C). The two most severely affected patients were homozygous for JW1. Three of 17 FGDS patients without CD were heterozygous for NOD2 risk variants.

Conclusion

Metallothioneins were significantly downregulated in non-inflamed terminal ileum of FGDS patients, but not in unrelated CD patients compared to controls. Downregulation of metallothioneins have previously been reported in IBD. Lower levels of these zinc binding proteins may interfere with NOD2-stimulated bacterial clearance and autophagy [3] . Further studies are warranted to investigate the role of these mechanisms in the susceptibility to CD in FGDS patients.

References:

[1] Fiskerstrand T, et al, (2012), Familial diarrhea syndrome caused by an activating GUCY2C mutation. , New England Journal of Medicine

[2] Jostins L, et al, (2012), Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease., Nature

[3] Lahiri A,Abraham C, (2014), Activation of Pattern Recognition Receptors Upregulates Metallothioneins, Thereby Increasing Intracellular Accumulation of Zinc, Autophagy, and Bacterial Clearance by Macrophages., Gastroenterology