We replicated the previously reported associations between CD and rs1000113 and rs4958847, confirming that IRGM is a susceptibility locus only for CD, either adult- or early-onset in the Italian population; furthermore, we have also shown its influence on specific clinical features (fistulizing disease).
This chapter reviews the recent literature on the roles of ATG16L1 and IRGM1 in the autophagy pathway, inflammation, antimicrobial immunity, and the biology of the intestine, and discusses how these genes may contribute to Crohn's disease pathogenesis.
Here we describe our recent studies into the Crohn disease-associated Immunity-Related GTPase family, M (IRGM) gene and our discovery of a large risk-conferring upstream deletion.
In particular, the importance of the innate immune system has been reaffirmed with the identification of IRGM and ATG16L1 genes in the autophagy pathway as CD susceptibility genes.
In conclusion, no evidence of association with CD has been reported for the Crohn's disease susceptibility polymorphisms studied in the NKX2-3, ATG16L1, and IRGM genes.
In conclusion, our results confirm the ATG16L1 rs2241880 and IRGMrs13361189 and rs4958847 polymorphisms as important markers for CD susceptibility and indicate that these variants are also associated with UC.
We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease.
Genome scans have robustly identified 11 susceptibility genes and loci and highlighted a number of new, previously unsuspected pathways as playing an important role in IBD pathogenesis-including the IL23 pathway in IBD overall and specific aspects of innate immunity (particularly NOD2 and the autophagy genes ATG16L1 and IRGM) in CD.
We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease.
These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant.
These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant.
One theoretical link between susceptibility genes NOD2/CARD15, ATG16L1, and IRGM is that CD is primarily induced by the presence of a dysfunctional immunological response to persistent infection by intracellular bacterial pathogens such as Mycobacterium avium subspecies paratuberculosis or adherent-invasive Escherichia coli, both first-rank candidates on the basis of host genetic susceptibility, which concerns impaired functions in the defense against intracellular bacteria.