P451. Phenotype–genotype profile in Crohn's disease predicted by genetic markers in autophagy-related genes

C. Duraes1, J.C. Machado1, F. Portela2, S. Rodrigues3, P. Lago4, M. Cravo5, M.P. Ministro dos Santos6, M. Marques7, I. Cremers8, J. Freitas9, J. Cotter10, L. Tavares11, L. Matos12, I. Medeiros13, R. Sousa14, J. Ramos15, J. Deus16, P. Caldeira17, C. Chagas18, M.A. Duarte19, R. Gonçalves20, R. Loureiro9, L. Barros21, I. Bastos22, E.M. Cancela23, M.C. Moraes24, M. Moreira10, A.I. Vieira9, F. Magro3

1Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; 2Coimbra University Hospital, Department of Gastroenterology, Coimbra, Portugal; 3Hospital De Sao João, Department of Gastroenterology, Porto, Portugal; 4Hospital De Santo António, Department of Gastroenterology, Porto, Portugal; 5Portuguese Institute of Oncology of Lisbon, Lisbon, Portugal; 6Viseu Hospital, Department of Gastroenterology, Viseu, Portugal; 7Hospital of Sao Joao, Porto, Portugal; 8Hospital of Sao Bernardo, Setubal, Portugal; 9Hospital Garcia De Orta, Department of Gastroenterology, Almada, Portugal; 10Hospital Guimaraes, Gastroenterology, Guimaraes, Portugal; 11Hospital of Santa Maria, Lisbon, Portugal; 12Hospital of Egas Moniz, Lisbon, Portugal; 13Hospital Espírito Santo De Évora Epe, Department of Gastroenterology, Évora, Portugal; 14Hospital of Amato Lusitano, Castelo Branco, Portugal; 15Hospital of Santo Antonio dos Capuchos, Lisbon, Portugal; 16Hospital Fernando Fonseca, Amadora, Portugal; 17Hospital of Faro, Faro, Portugal; 18Hospital of Santa Cruz, Oeiras, Portugal; 19Hospital of Divino Espirito Santo, Ponta Delgada, Portugal; 20Hospital of São Marcos, Braga, Portugal; 21Hospital of Padre Americo, Penafiel, Portugal; 22Hospital of Infante D. Pedro, Aveiro, Portugal; 23Hospital São Teotónio Viseu, Department of Gastroenterology, Sever Do Vouga, Portugal; 24Hospital of Portimao, Portimao, Portugal

Background: Host genetics plays an important role in the pathogenesis of Crohn's disease (CD). Many loci have been associated with susceptibility to CD particularly in pathways of innate immunity, autophagy, pathogen recognition and epithelial barrier function. Most studies have been equivocal in the discovery of phenotype–genotype associations, and prediction of specific disease clinical outcomes and therapy response is still lacking.

Methods: CD susceptibility genetic variants linked with homeostatic mechanisms ATG16L1 rs2241880, ICAM1 rs5498, IL4 rs2070874, IL17F rs763780, IRGM rs13361189, ITLN1 rs2274910, LRRK2 rs11175593 and TLR4 rs4986790 were investigated in a portuguese population (511 patients, 626 controls). The same SNPs were assessed for association with clinical outcomes and response to therapy.

Results: Considering a recessive model there is a significant association of CD with the autophagy-linked SNPs in ATG16L1 [OR (p-value), respectively 1.87 (2.3×10−4), 2.26 (0.04) and 1.64 (0.03)]. These SNPs are associated, in the log-additive model, with ileal location [OR (p-value), respectively, 1.49 (5.3×10−4), 1.52 (0.01) and 1.70 (1.4×10−4)], ileocolonic location [OR (p-value), respectively, 1.31 (0.01), 1.57 (2.4×10−3) and 1.68 (4.4×10−5)], involvement of the upper digestive tract [OR (p-value), respectively for ATG16L1 and IRGM, 1.96 (6.4×10−3) and 1.95 (0.03)]. There is an increased risk for ileal disease, with or without colonic involvement, and the upper digestive tract location when the genotypic models are considered. The risk genotype GG in ATG16L1 is associated with patients which are not steroid-resistant [OR (p-value) 1.89 (5.3×10−4)], respond to immunosuppressants [OR (p-value) 1.77 (0.01)] and to biologic therapy [OR (p-value) 1.89 (0.01)]. The SNPs in ITLN1 and IRGM are both associated with a positive response to biologic therapy [OR (p-value) for CC in IRGM is 3.09 (0.02) and for ITLN1 in the log-additive model is 1.49 (9.6×10−3)]. The risk for ileal, ileocolonic and upper digestive tract locations increases with the number of risk alleles [OR (p-value) for 3 risk alleles, respectively, 7.10 (7.8×10−5), 3.54 (9.4×10−4) and 12.07 (0.02)]. The OR (p-value) for positive response to biologic therapy is 3.66 (0.01) when 3 risk alleles are present.

Conclusions: A multi-locus approach with the autophagy genes ATG16L1, IRGM and ITLN1 provides insights into phenotype–genotype associations in CD and identifies genetic profiles that may tailor treatment selection to benefit patients.