Genetics of inflammatory bowel disease from multifactorial to monogenic forms

Abstract

Inflammatory bowel disease (IBD) is a group of chronic multifactorial disorders. According to a recent study, the number of IBD association loci is increased to 201, of which 37 and 27 loci contribute specifically to the development of Crohn’s disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity, in the autophagy and in the inflammatory response such as NOD2, ATG16L1 and IL23R, while other are implicated in immune mediated disease (STAT3) and in susceptibility to mycobacterium infection (IL12B). In case of early onset of IBD (VEO-IBD) within the 6^th year of age, the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies.

Keywords: Inflammatory bowel disease; Primary immunodeficiency disease; Early onset; Next generation sequencing; Genome wide association studies

Core tip: Genetic investigation is of fundamental importance describing inflammatory bowel disease (IBD) as a complex disease, as well as in identifying the monogenic disorders that may present with IBD-like features. Using third-generation technology should be leveraged to accelerate the screening and allow the identification of the most rare monogenic defects. Furthermore, the study of genetic variants in monogenic and in sporadic IBD could help unraveling the complex interplay between defective and compensatory immune responses, opening the way to the identification of new targets for therapy.