Extraintestinal Manifestations and Complications in Inflammatory Bowel Disease: From Shared Genetics to Shared Biological Pathways

Suzanne van Sommeren, Marcel Janse, Juha Karjalainen, Rudolf Fehrmann, Lude Franke, Jingyuan Fu, Rinse K. Weersma*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)987-994
Number of pages8
JournalInflammatory Bowel Diseases
Volume20
Issue number6
DOIs
Publication statusPublished - Jun-2014

Keywords

  • extraintestinal manifestations
  • complications
  • inflammatory bowel disease
  • genetic risk
  • biological pathways
  • GENOME-WIDE ASSOCIATION
  • BONE-MINERAL DENSITY
  • PRIMARY SCLEROSING CHOLANGITIS
  • CANCER SUSCEPTIBILITY LOCUS
  • COLORECTAL-CANCER
  • RISK LOCI
  • ULCERATIVE-COLITIS
  • SEQUENCE VARIANTS
  • CROHNS-DISEASE
  • SCAN

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