Down the line from genome-wide association studies in inflammatory bowel disease: the resulting clinical benefits and the outlook for the future

Abstract

Inflammatory bowel disease (IBD), consisting of Crohn’s disease and ulcerative colitis, is a chronic inflammatory disease of the gut. The etiology of IBD is complex, involving genetic as well as environmental factors. Genetic studies have identified 163 genetic risk loci for IBD, which have led to new insights into the biological mechanisms of the disease. The currently known IBD risk loci show an almost 75% overlap with genetic risk loci for other immune mediated diseases. Current studies are focused on the translation of the identified risk loci to clinical practice. The first steps towards this translation are being taken with the identification of genetic risk factors for drugs toxicity, specific disease course and response to therapy. In this review we will discuss how the IBD genetic risk loci were identified and how this knowledge can be translated towards clinical practice.

Keywords:

• crohn’s disease
• drug targets
• GWAS
• immune mediated diseases
• immunochip
• inflammatory bowel disease
• risk models
• ulcerative colitis

Financial & competing interests disclosure

LMS, MCV, RKW and EAF worked on the content of the paper The first draft of the manuscript was written by LMS, MCV and EAF. All authors contributed to the final manuscript.

Weersma RK is supported by a VIDI grant (016.136.308) from the Netherlands Organization for Scientific Research (NWO). Visschedijk MC is supported by an AGIKO grant (92.003.577) from The Netherlands Organization for Scientific Research (NWO). Festen EAM is supported with a Mandema stipend from the University Medical Centre Groningen (UMCG), University of Groningen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Inflammatory bowel diseases (IBD), consisting of ulcerative colitis (UC) and Crohn’s disease (CD), are chronic inflammatory diseases with a complex pathogenesis, originating from an aberrant immune response to the commensal intestinal bacterial flora in a genetically susceptible host.

• Genome-wide association studies identified 163 genetic risk variants for IBD, which account for 4,1-13,5% of disease risk variance.

• Genetic studies have led to the identification of ATG16L1, IRGM and NOD2 as CD risk genes, thus showing the importance of the process of autophagy in CD pathogenesis.

• Almost three-quarters of the IBD genetic risk loci were found to be overlapping with other immune mediated diseases.

• The IL23 pathway has been the most extensively studied risk pathway for inflammatory disease; variants around this gene seem to give rise to a range of different immune mediated phenotypes.

• Fine-mapping of genetic risk loci and sequencing of genetic risk loci in IBD cases and healthy controls is currently being performed and will lead to better understanding of the causal link between the IBD associated common genetic variants and the disease mechanism.

• The newly identified IBD risk loci and biological mechanisms are suitable targets for drug therapy and several new drugs are emerging targeting these mechanisms

• The new insights in IBD pathogenesis gained through molecular research will lead to the realization of personalized medicine: adapting treatment to the individual patient based on his or her genetic profile.