This interest has been substantiated by genome-wide association studies with the identification of genetic association between Crohn's disease and variants in two separate autophagy genes, ATG16L1 and IRGM.
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.
The autophagy pathway has been linked with Crohn's disease (CD) through association of the ATG16L1 and IRGM genes with susceptibility for CD, and also to the Nod2 pathway, involved in CD.
IRGMrs72553867 exhibited association with CD with respect to its minor allele frequency (OR 0.50, 95% CI 0.27-0.91, P = 0.02) and genotype distribution (dominant model: OR 0.50, 95% CI 0.23-0.94, P = 0.03).
The associated polymorphisms in ATG16L1 and IRGM have been confirmed, and functional studies have begun to shed light on how they link to CD pathogenesis.
Autophagy-related 16 like-1 (ATG16L-1), immunity-related GTPase-M (IRGM), and nucleotide-binding oligomerization domain-containing 2 (NOD2) regulate autophagy, and variants in these genes have been associated with predisposition to Crohn's disease (CD).
: Single-nucleotide polymorphism rs4958847 in the IRGM gene correlated very significantly with frequency of surgery in patients with ileocolonic Crohn's disease.
Colon-only CD (n = 228) was compared with healthy controls: three of six UC SNPs (in MST1, HLA-DRA, and IL-23R) and 11 of 34 CD SNPs: in IRGM, NOD2 (rs2066845), CCNY, MST1, IL23R, PTPN22, C11orf30, ZNF365, PTPN2, PSMG1, and rs1456893 were significantly associated.
IRGM SNP rs10065172 was significantly associated with CD susceptibility in terms of allelic frequency (P = 0.004; odds ratio [OR] = 1.42) and genotype frequency (dominant model, P = 0.008; OR = 1.62).
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.
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).