Genotyping for ATG16L1, NOD2/CARD15, and IRGM1 was performed in 80 consecutive patients with Crohn's disease (median age: 11 years; range: 0.7-17.9 years).
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.
Here we report an integrative analysis of an expanded number of Crohn's disease (CD) related genetic defects in innate immune function (NOD2, ATG16L1, IRGM, CARD9, XBP1, ORMDL3) and composition of the ileal microbiome by combining the initial patient cohort (Batch 1, 2005-2010, n = 165) with a second consecutive patient cohort (Batch 2, 2010-2012, n = 118).
Impaired Paneth cell expression of antimicrobial protein (AMP) lysozyme is found in patients with Crohn's disease with the autophagy gene ATG16L1 risk allele, in mice with mutations in autophagy genes Atg16L1, Atg5 and Atg7, and in Irgm1 knockout mice.
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.
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 recent years considerable advances in understanding the pathogenesis of Crohn disease have been achieved, with the identification of susceptibility variants of genes that are part of the autophagy machinery, i.e., ATG16L1 and IRGM.
In this review, we summarize recent studies on the CD-associated NOD2, ATG16L1 and IRGM risk variants and their contribution to the autophagy functions that have most influenced our understanding of CD pathophysiology.
Indeed, genes important in the regulation of the IL-17-IL-23 pathway and, in Crohn's disease, genes important for autophagy (that is, NOD2 and ATG16L1 and IRGM) have a role in conferring susceptibility of individuals to these diseases.
None of the so-called predisposing alleles of IRGM gene predispose Iranians to Crohn's disease while the prevalence of some of them like CNV deletion was higher in normal controls.
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.
Our results confirm IRGM as susceptibility gene for CD in the German population, supporting a role for the autophagy genes IRGM and ATG16L1 in the pathogenesis of CD.
Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.Nat.Gen. 39: (7), 830-832.), and show that the estimated ORs can vary substantially if both selection and correlation are taken into account.
Several combinations of genetic predisposing factors to CD have been described, with the most significant replicable associations including genes for intracellular receptor of bacterial cell walls (NOD2/CARD15), and for bacterial clearance and antigen processing through autophagy (ATG16L1 and IRGM).