• Cecília Durães, José C Machado, Francisco Portela, Susana Rodrigues, Paula Lago, Marília Cravo, Paula Ministro, Margarida Marques, Isabelle Cremers, João Freitas, José Cotter, Lurdes Tavares, Leopoldo Matos, Isabel Medeiros, Rui Sousa, Jaime Ramos, João Deus, Paulo Caldeira, Cristina Chagas, Maria A Duarte, Raquel Gonçalves, Rui Loureiro, Luísa Barros, Isabel Bastos, Eugénia Cancela, Mário C Moraes, Maria J Moreira, Ana I Vieira, and Fernando Magro.
• Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.
• Inflamm. Bowel Dis. 2013 Feb 1; 19 (2): 230-9.

BackgroundAbout 70 loci are associated with susceptibility to Crohn's disease (CD), particularly in pathways of innate immunity, autophagy, and pathogen recognition. Phenotype-genotype associations are inconsistent.MethodsCD susceptibility polymorphisms ATG16L1 rs2241880, ICAM1 rs5498, IL4 rs2070874, IL17F rs763780, IRGM rs13361189, ITLN1 rs2274910, LRRK2 rs11175593, and TLR4 rs4986790 were genotyped in a Portuguese population (511 CD patients, 626 controls) and assessed for association with CD clinical characteristics.ResultsThere 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). These SNPs are associated with ileal location (OR, respectively, 1.49, 1.52, and 1.70), ileocolonic location (OR, respectively, 1.31, 1.57, and 1.68), and involvement of the upper digestive tract (OR, respectively for ATG16L1 and IRGM, 1.96 and 1.95). The risk genotype GG in ATG16L1 is associated with patients who respond to steroids (OR 1.89), respond to immunosuppressants (OR 1.77), and to biologic therapy (OR 1.89). The SNPs in ITLN1 and IRGM are both associated with a positive response to biologic therapy. The risk for ileal, ileocolonic, and upper digestive tract locations increases with the number of risk alleles (OR for three alleles, respectively, 7.10, 3.54, and 12.07); the OR for positive response to biologic therapy is 3.66.ConclusionsA multilocus approach using autophagy-related genes provides insight into CD phenotype-genotype associations and genetic markers for predicting therapeutic responses.

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