Background: About 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.
Methods: CD 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.
Results: 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 × 10−4 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 × 10−6 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.
Conclusions: A multilocus approach using autophagy-related genes provides insight into CD phenotype–genotype associations and genetic markers for predicting therapeutic responses.
Article first published online 9 May 2012
1Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
2Faculty of Medicine of the University of Porto, Porto, Portugal
3Hospital of the University of Coimbra, Coimbra, Portugal
4Hospital of São João, Porto, Portugal
5Hospital of Santo António, Porto, Portugal
6Portuguese Institute of Oncology of Lisbon, Lisbon, Portugal
7Hospital of São Teotónio, Viseu, Portugal
8Hospital of São Bernardo, Setúbal, Portugal
9Hospital of Garcia de Orta, Almada, Portugal
10Hospital Centre of Alto Ave, Guimarães, Portugal
11Hospital of Santa Maria, Lisbon, Portugal
12Hospital of Egas Moniz, Lisbon, Portugal
13Hospital of Évora, Évora, Portugal
14Hospital of Amato Lusitano, Castelo Branco, Portugal
15Hospital of Santo António dos Capuchos, Lisbon, Portugal
16Hospital of Prof. Dr Fernando Fonseca, Amadora, Portugal
17Hospital of Faro, Faro, Portugal
18Hospital of Santa Cruz, Oeiras, Portugal
19Hospital of Divino Espírito Santo, Ponta Delgada, Portugal
20Hospital of São Marcos, Braga, Portugal
21Hospital of Padre Américo, Penafiel, Portugal
22Hospital of Infante D. Pedro, Aveiro, Portugal
23Hospital of Portimão, Portimão, Portugal
24Institute for Molecular and Cell Biology of the Universiy of Porto, Porto, Portugal.
Reprints: Prof. Fernando Magro, Department of Pharmacology and Therapeutics, Faculty of Medicine of the University of Porto, Alameda Prof. Hernani Monteiro 4200-319 Porto, Portugal (e-mail: firstname.lastname@example.org).
Supported by the Portuguese Inflammatory Bowel Disease Group (GEDII 2009 Research Grant); Cecília Durães is supported by the Portuguese Foundation for Science and Technology grant SFRH/BPD/62974/2009. IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by the Portuguese Foundation for Science and Technology.
Received March 13, 2012
Accepted April 12, 2012