Novel association of the interleukin 2-interleukin 21 region with inflammatory bowel disease.
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.
Márquez
Ana
A
Immunology Department, Hospital Clínico San Carlos, Madrid 28040, Spain.
Orozco
Gisela
G
Martínez
Alfonso
A
Palomino-Morales
Rogelio
R
Fernández-Arquero
Miguel
M
Mendoza
Juan Luis
JL
Taxonera
Carlos
C
Díaz-Rubio
Manuel
M
Gómez-García
María
M
Nieto
Antonio
A
López-Nevot
Miguel A
MA
de la Concha
Emilio G
EG
Martín
Javier
J
Urcelay
Elena
E
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
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