title: Extraintestinal manifestations and complications in inflammatory bowel disease: from shared genetics to shared biological pathways.
abstract: BACKGROUND
  The clinical presentation of the inflammatory bowel diseases (IBD) is extremely heterogenous and is characterized by various extraintestinal manifestations and complications (EIM). Increasing genetic insight for IBD and EIM shows multiple shared susceptibility loci. We hypothesize that, next to these overlapping genetic risk loci, distinct disease pathways are shared between IBD and EIM.
  
  
  METHODS
  The overlapping genetic risk loci for IBD and its EIM were searched in literature. We assessed shared disease pathways by performing an extensive pathway analysis by protein-protein interaction and cotranscriptional analysis, using both publicly available and newly developed databases.
  
  
  RESULTS
  Reliable genetic data were available for primary sclerosing cholangitis, ankylosing spondylitis, decreased bone mineral density, colorectal carcinoma, gallstones, kidney stones, and deep venous thrombosis. We found an extensive overlap in genetic risk loci, especially for IBD and primary sclerosing cholangitis and ankylosing spondylitis. We identified 370 protein-protein interactions, of which 108 are statistically specific. We identified 446 statistically specific cotranscribed gene pairs. The interactions are shown to cluster in specific biological pathways.
  
  
  CONCLUSIONS
  We show that the pathogenetic overlap between IBD and its EIM extends beyond shared risk genes to distinctive shared biological pathways. We define genetic background as a risk factor for IBD-EIM alongside known mechanisms such as malabsorption and medication. Clustering patients based on distinctive pathways may enable stratification of patients to predict development of EIM.
authors.affiliation: Departments of *Genetics, and †Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: van Sommeren
authors.forename: Marcel
authors.initials: M
authors.lastname: Janse
authors.forename: Juha
authors.initials: J
authors.lastname: Karjalainen
authors.forename: Rudolf
authors.initials: R
authors.lastname: Fehrmann
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fu
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
mesh_terms: D015209:Cholangitis, Sclerosing / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D002874:Chromosome Mapping; D015179:Colorectal Neoplasms / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D042882:Gallstones / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D053040:Nephrolithiasis / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D012307:Risk Factors; D013167:Spondylitis, Ankylosing / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D020246:Venous Thrombosis / Q000150:complications / Q000453:epidemiology / Q000235:genetics