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Advances in IBD genetics

Key Points

  • The Immunochip project has identified >160 loci containing IBD genes and 70% of these loci are shared with other immune-mediated inflammatory diseases

  • Similar to other complex polygenic diseases, only a small fraction of heritability is explained by the genetic loci identified in IBD

  • Hypothesis-free genetic association studies in IBD have identified key pathways involved in innate immunity, autophagy, lymphocyte differentiation and chemotaxis

  • Genetic corroboration is now available for novel treatment strategies targeting IL-12–IL-23 signalling, JAK–STAT signalling and leukocyte chemotaxis

  • The paradigm of personalized IBD care will probably only be achieved if we succeed in integrating the genetic and basic science advances with insights into the ecology of the gut microbiota

Abstract

IBD is a spectrum of chronic disorders that constitute an important health problem worldwide. The hunt for genetic determinants of disease onset and course has culminated in the Immunochip project, which has identified >160 loci containing IBD susceptibility genes. In this Review, we highlight how genetic association studies have informed our understanding of the pathogenesis of IBD by focusing research efforts on key pathways involved in innate immunity, autophagy, lymphocyte differentiation and chemotaxis. Several of these novel genetic markers and cellular pathways are promising candidates for patient stratification and therapeutic targeting.

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Figure 1: The complex polygenic pathogenesis of IBD.
Figure 2: NOD2 structure and position of the most common variants with Crohn's disease.71
Figure 3: Paneth cells as the site of origin of intestinal crypt inflammation as well as crypt homeostasis.

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Acknowledgements

J.V.L. acknowledges support from the North American Society for Paediatric Gastroenterology, Hepatology and Nutrition Foundation and Crohn's & Colitis Foundation of America Young Investigator Development Award 2013.

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Prioritized candidate genes on IBD susceptibility loci. (DOC 40 kb)

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Van Limbergen, J., Radford-Smith, G. & Satsangi, J. Advances in IBD genetics. Nat Rev Gastroenterol Hepatol 11, 372–385 (2014). https://doi.org/10.1038/nrgastro.2014.27

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