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).
Taken together, our findings suggest that genetically encoded IRGM deficiency may predispose to CD through dysregulation of inflammatory gene networks.
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.
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.
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.
For CD patients, laboratory data were correlated with clinical phenotype, use of immunomodulation, and CD risk alleles (NOD2, IL-23R, ATG16L1 and IRGM).
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).
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).
The IRGM gene was amplified in four segments and Sanger-sequenced in 101 participants (42 Crohn's disease, 39 ulcerative colitis, and 20 healthy controls).
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.
There is a significant association of CD with the single nucleotide polymorphisms (SNPs) in ATG16L1 (odds ratio [OR] 1.36 [1.15-1.60], P = 2.7 × 10(-6) for allele G), IRGM (OR 1.56 [1.21-1.93], P = 3.9 × 10(-4) for allele C), and ITLN1 (OR 1.55 [1.28-1.88], P = 4.9 × 10(-4) for allele C).
Genetic variations involved in the innate immune system (NOD2, ATG16L1, and IRGM) showed no association with CD susceptibility in the Japanese population.