Rune R Tronstad1,2, Tatiana Polushina3,4, Hans-Richard Brattbakk3,4, Christine Stansberg3,4, Hilde Løland von Volkmann5,6, Kurt Hanevik1, Eva Ellinghaus7,8, Silje Fjellgård Jørgensen8,9, Kari Merete Ersland3,4, Khanh D-C Pham6, Odd Helge Gilja5,10, Nils Hovdenak6, Trygve Hausken5,6, Morten H Vatn11,12, Andre Franke7, Per Morten Knappskog1,13, Stephanie Le Hellard3,4, Tom Hemming Karlsen8,14,15, Torunn Fiskerstrand1,13. 1. a Department of Clinical Science , University of Bergen , Bergen , Norway. 2. b Department of Paediatrics , Haukeland University Hospital , Bergen , Norway. 3. c NORMENT- K.G. Jebsen Center for Psychosis Research, Department of Clinical Science , University of Bergen , Bergen , Norway. 4. d Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics , Haukeland University Hospital , Bergen , Norway. 5. e Department of Clinical Medicine , University of Bergen , Bergen , Norway. 6. f Department of Medicine , Haukeland University Hospital , Bergen , Norway. 7. g Institute of Clinical Molecular Biology , Christian Albrechts University of Kiel , Kiel , Germany. 8. h K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine , University of Oslo , Oslo , Norway. 9. i Section of Clinical Immunology and Infectious Diseases, Department of Rheumatology, Dermatology and Infectious Diseases , Oslo University Hospital , Rikshospitalet , Oslo , Norway. 10. j National Centre for Ultrasound in Gastroenterology , Haukeland University Hospital , Bergen , Norway. 11. k Department of Clinical Molecular Biology and Laboratory Sciences (EpiGen), Division of Medicine , Akershus University Hospital and. 12. l Medical Clinic , Oslo University Hospital Rikshospitalet Oslo , Oslo , Norway. 13. m Department of Medical Genetics , Haukeland University Hospital , Bergen , Norway. 14. n Research Institute of Internal Medicine , Oslo University Hospital Rikshospitalet , Oslo , Norway. 15. o Norwegian PSC Research Centre at the Department of Transplantation Medicine, Division of Cancer medicine, Surgery and Transplantation , Oslo University Hospital , Oslo , Norway.
Abstract
OBJECTIVE: Activating mutations in the GUCY2C gene, which encodes the epithelial receptor guanylate cyclase C, cause diarrhea due to increased loss of sodium chloride to the intestinal lumen. Patients with familial GUCY2C diarrhea syndrome (FGDS) are predisposed to inflammatory bowel disease (IBD). We investigated whether genes in the guanylate cyclase C pathway are enriched for association with IBD and reversely whether genetic or transcriptional changes associated with IBD are found in FGDS patients. METHODS: (1) A set of 27 genes from the guanylate cyclase C pathway was tested for enrichment of association with IBD by Gene Set Enrichment Analysis, using genome-wide association summary statistics from 12,882 IBD patients and 21,770 controls. (2) We genotyped 163 known IBD risk loci and sequenced NOD2 in 22 patients with FGDS. Eight of them had concomitant Crohn's disease. (3) Global gene expression analysis was performed in ileal tissue from patients with FGDS, Crohn's disease and healthy individuals. RESULTS: The guanylate cyclase C gene set showed a significant enrichment of association in IBD genome-wide association data. Risk variants in NOD2 were found in 7/8 FGDS patients with concomitant Crohn's disease and in 2/14 FDGS patients without Crohn's disease. In ileal tissue, downregulation of metallothioneins characterized FGDS patients compared to healthy controls. CONCLUSIONS: Our results support a role of guanylate cyclase C signaling and disturbed electrolyte homeostasis in development of IBD. Furthermore, downregulation of metallothioneins in the ileal mucosa of FGDS patients may contribute to IBD development, possibly alongside effects from NOD2 risk variants.
OBJECTIVE: Activating mutations in the GUCY2C gene, which encodes the epithelial receptor guanylate cyclase C, cause diarrhea due to increased loss of sodium chloride to the intestinal lumen. Patients with familial GUCY2C diarrhea syndrome (FGDS) are predisposed to inflammatory bowel disease (IBD). We investigated whether genes in the guanylate cyclase C pathway are enriched for association with IBD and reversely whether genetic or transcriptional changes associated with IBD are found in FGDS patients. METHODS: (1) A set of 27 genes from the guanylate cyclase C pathway was tested for enrichment of association with IBD by Gene Set Enrichment Analysis, using genome-wide association summary statistics from 12,882 IBD patients and 21,770 controls. (2) We genotyped 163 known IBD risk loci and sequenced NOD2 in 22 patients with FGDS. Eight of them had concomitant Crohn's disease. (3) Global gene expression analysis was performed in ileal tissue from patients with FGDS, Crohn's disease and healthy individuals. RESULTS: The guanylate cyclase C gene set showed a significant enrichment of association in IBD genome-wide association data. Risk variants in NOD2 were found in 7/8 FGDS patients with concomitant Crohn's disease and in 2/14 FDGS patients without Crohn's disease. In ileal tissue, downregulation of metallothioneins characterized FGDS patients compared to healthy controls. CONCLUSIONS: Our results support a role of guanylate cyclase C signaling and disturbed electrolyte homeostasis in development of IBD. Furthermore, downregulation of metallothioneins in the ileal mucosa of FGDS patients may contribute to IBD development, possibly alongside effects from NOD2 risk variants.
Authors: Natalya I Motyka; Sydney R Stewart; Ian E Hollifield; Thomas R Kyllo; Joshua A Mansfield; Elizabeth B Norton; John D Clements; Jacob P Bitoun Journal: Infect Immun Date: 2021-03-17 Impact factor: 3.441