Background and aims: Granulomas are a characteristic microscopic finding in Crohn's disease. Their clinical significance is controversial and their pathogenesis is unknown, but impaired processing of bacterial components has been suggested. Autophagy is a fundamental process involved in the elimination of intracellular bacteria. Genetic variants in autophagy genes IRGM and ATG16L1 have been associated with susceptibility to Crohn's disease. We therefore investigated whether variants in autophagy genes contribute to granuloma formation.

Methods: Surgical specimens from 464 clinically well-documented Crohn's patients were reviewed and scored for the presence and distribution of granulomas. All patients were genotyped for the CD-associated SNPs in ATG16L1 and IRGM as well as for 77 haplotype tagging SNPs in 13 additional autophagy genes.

Results: Granulomas were found in 75% of the patients. Their frequency increased with more distal involvement of the GI tract. Granuloma positive patients were significantly younger at the time of diagnosis and surgery, and were more likely to smoke. We identified associations between granulomas and autophagy gene variants ATG4A (rs5973822), FNBP1L (rs17109951) and ATG4D (rs7248026; rs2304165; rs10439163).

Conclusion: These findings suggest that granuloma formation is a marker of a more aggressive disease course, and that variants in autophagy genes ATG4A , ATG2A , FNBP1L and ATG4D , may contribute to granuloma formation.

Highlights: ► Granulomas are a marker of aggressive clinical behavior. ► Young patients develop granulomas more frequently with more granulomas in the bowel wall. ► Smokers are more likely to develop granulomas. ► Autophagy genes ATG4A , FNBP1L and ATG4D are associated with granuloma formation.