title: Novel association of the interleukin 2-interleukin 21 region with inflammatory bowel disease.
abstract: OBJECTIVE
  Genome-wide association studies have reported the role of the interleukin (IL) 2-IL21 chromosomal region at 4q27 in several autoimmune conditions. Mice deficient in IL-2 develop a disease with clinical and histological similarity to ulcerative colitis (UC) in humans. Modest evidence of linkage with UC was tentatively proposed for the IL2 gene more than a decade ago. Therefore, we decide to investigate the association of polymorphisms in the IL-2 axis (IL2, IL2RA, and IL2RB genes) with inflammatory bowel diseases (IBDs).
  
  
  METHODS
  Seven hundred and twenty-eight white Spanish unrelated IBD patients (356 Crohn's disease (CD) and 372 UC) and 549 ethnically matched controls were included in a case-control study. In addition, a Spanish replication cohort with 562 CD and 430 UC patients and 1,310 controls were analyzed. Eight single-nucleotide polymorphisms previously associated with different autoimmune diseases were analyzed using TaqMan chemistry.
  
  
  RESULTS
  The IL2-rs6822844 polymorphism modified CD predisposition (P=0.002; odds ratio, OR (95% confidence interval, CI)=0.61 (0.44-0.84)); this was replicated in the other Spanish cohort, resulting in a strong protective effect of the minor allele in the merged samples (P=0.0002; OR (95% CI)=0.70 (0.58-0.85)). A similar effect of rs6822844 was detected for UC. Another marker, rs11938795, also showed evidence of an association with CD (P=0.006; OR (95% CI)=0.73 (0.58-0.92)).
  
  
  CONCLUSIONS
  Polymorphisms within the IL2-IL21 linkage disequilibrium (LD) block show a novel association with IBD, this is concordant with suggestive previous results of whole genome analyses in CD and type 1 diabetes. Our data agree with the effect previously observed for other conditions and delineate a shared underlying mechanism.
authors.affiliation: Immunology Department, Hospital Clínico San Carlos, Madrid 28040, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Márquez
authors.forename: Gisela
authors.initials: G
authors.lastname: Orozco
authors.forename: Alfonso
authors.initials: A
authors.lastname: Martínez
authors.forename: Rogelio
authors.initials: R
authors.lastname: Palomino-Morales
authors.forename: Miguel
authors.initials: M
authors.lastname: Fernández-Arquero
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Mendoza
authors.forename: Carlos
authors.initials: C
authors.lastname: Taxonera
authors.forename: Manuel
authors.initials: M
authors.lastname: Díaz-Rubio
authors.forename: María
authors.initials: M
authors.lastname: Gómez-García
authors.forename: Antonio
authors.initials: A
authors.lastname: Nieto
authors.forename: Miguel A
authors.initials: MA
authors.lastname: López-Nevot
authors.forename: Emilio G
authors.initials: EG
authors.lastname: de la Concha
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
mesh_terms: D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics; D007378:Interleukins / Q000235:genetics*; D011110:Polymorphism, Genetic; D013030:Spain; D000098546:Interleukin-21
chemical_list: C508017:IL2RA protein, human; C508020:IL2RB protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053646:Interleukin-2 Receptor beta Subunit; D007378:Interleukins; D000098546:Interleukin-21