Correlation between ATG16L1 and NOD2 Gene Crohn's Disease-Associated Risk Alleles with Abnormal Ileal Paneth Cell Morphology
W Cao, EC Boedecker, DN Frank, K Cadwell, L Mayer, TS Stappenbeck, RB Sartor, E Li, N Harpaz. Mt. Sinai School of Medicine, New York; U. of Washington, St. Louis; U. of Colorado, Denver; U. of New Mexico, Albequerque; U. of N. Carolina, Chapel Hill
Background: ATG16L1, an autophagy gene, and NOD2, an intracellular pattern recognition receptor, are 2 of >30 known susceptibility genes for Crohn's disease (CD). Although the relationships between their respective functions and the pathology of CD are not yet fully understood, they have been associated with defective Paneth cell (PC) bacterial defense and/or homeostasis. The association between ATG16L1 (T300A) homozygosity and impaired PC function in humans is reflected in morphologic alterations that include disorganized or diminished cytoplasmic granules. In this study we investigated whether NOD2 risk alleles alone or in combination with ATG16L1 result in PC abnormalities and whether they depend on the patient's IBD status.
Design: We evaluated the morphologic features of uninflamed H&E-stained ileal sections from surgical resection specimens of 60 patients (24 CD, 17 ulcerative colitis (UC) and 19 non-IBD controls) with known genotypes for >30 CD-associated risk alleles including the 3 major NOD2 SNPs (Leu1007fs, R702W and G908R) and the ATG16L1 T300A SNP. These features included the density, homogeneity and intensity of staining of PC granules, which were graded as normal or abnormal.
Results: Among 19 ATG16L1 homozygotes (8/24 CD, 4/17 UC, 7/19 controls), PC abnormalities occurred in 8 (100%) with CD, 3 (75%) with UC and 3 (43%) controls. PC abnormalities occurred in all of 3 patients who were homozygous for NOD2 risk alleles and wild type for ATG16L1 (all CD), in 1 patient (UC) who was homozygous for both risk alleles, and in all of 5 NOD2/ATG16L1 double heterozygotes (3 CD, 2 UC). Of 16 wild type patients (5 CD, 4 UC and 7 NM), PC abnormalities occurred in 2 (1 UC, 1 control; p=0.004). No enterocyte abnormalities were observed in any of the cases.
Conclusions: Abnormal PC morphology is associated with the ATG16L1 and NOD2 CD-associated risk alleles either alone or in combination. Importantly, this finding does not correlate with the presence or absence of IBD.
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 62, Wednesday Morning