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In the past decade, we have witnessed enormous progress in the understanding of the genetics of inflammatory bowel diseases (IBD), resulting in the discovery and confirmation of 163 IBD susceptibility regions by the end of 20121–3 which is the highest number of susceptibility genes discovered for any complex disease so far. However, clinically highly relevant gene associations are still very limited, thereby also limiting the use of genetic information in the current treatment of IBD patients. The European IBDchip project4 represents a large detailed genotype-phenotype analysis of IBD patients and starts to fill the gap between IBD genetics and clinically relevant information.
This European multicentre study analysed more than 1500 patients with Crohn's disease (CD) for CD susceptibility variants, identified in the meta-analysis of genome-wide association studies (GWAS) by Barrett et al,5 regarding predictors for CD outcomes such as disease localisation and disease behaviour.4 The main result of this study was the identification of NOD2 as the most important genetic predictor for ileal disease, ileal stenoses, fistula and CD-related surgery. This confirms previous reports showing particularly strong associations with ileal involvement, ileal stenosis and need for surgery in patients homozygous for the p.Leu1007fsX1008 NOD2 variant.6 ,7 An inadequate immune response to bacterial antigens in patients with mutated NOD2 gene resulting in chronic ileal inflammation seems to be the starting point for a sequel of events leading to ileal stenoses and thereby increasing the risk for fistula formation,8 finally requiring surgery.6
Janus kinase 2 (JAK2) was the other gene significantly associated with ileocolonic disease involvement and stenosing disease behaviour, although the disease associations with JAK2 were weaker than that with NOD2.4 JAK2 is a key component of the signal transduction pathway of several cytokines including interleukin (IL)-12 and IL-23 which …
Funding SB was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (BR 1912/6-1) and the Else Kröner-Fresenius-Stiftung (Else Kröner-Exzellenzstipendium 2010_EKES.32).
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.