NOD2/CARD15 and TNFA, but not IL1B and IL1RN, are associated with Crohn's disease.
BACKGROUND
NOD2/CARD15 was described as the first susceptibility gene to Crohn's disease (CD). Polymorphisms in the TNFA gene and in the IL1 gene cluster, which are associated with an enhanced chronic inflammatory response, may also play a role in the development of CD. The aim of this study was to determine the association of polymorphisms in the CARD15, TNFA, IL1B, and IL1RN genes with risk of development of CD and with the clinicopathological profile of CD patients.


METHODS
In a case-control study including 235 CD patients and 312 controls (929 controls for TNFA genotyping), the CARD15 (R702W, G908R, and 1007fs), TNFA (-308G/A and -857C/T), IL1B (-511C/T), and IL1RN (intron 2 variable number of tandem repeats) polymorphisms were genotyped.


RESULTS
We observed a significant association between CD and the CARD15 polymorphisms, with an odds ratio (OR) of 2.9 [95% confidence interval (CI), 1.9 to 4.6] for carriers of 1 variant allele and an OR of 11.8 (95% CI, 3.5 to 40.4) for carriers of 2 variant alleles. Patients with CARD15 polymorphisms had more frequently ileal or ileocolonic disease location, stricturing phenotype, abdominal surgery, and no extraintestinal manifestations. The TNFA-308A/A genotype was associated with susceptibility to CD with an OR of 3.0 (95% CI, 1.2 to 7.2). TNFA-308A/A homozygotes showed a higher frequency of erythema nodosum and arthritis, colonic disease location, and absence of abdominal surgery. No associations were found with the TNFA-857, IL1B-511, and the IL1RN VNTR polymorphisms.


CONCLUSIONS
These findings suggest that CARD15 and TNFA-308 genetic polymorphisms are associated with increased risk of CD displaying distinct clinicopathological profiles.
Ferreira
António Carlos
AC
Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.
Almeida
Susana
S
Tavares
Marta
M
Canedo
Paulo
P
Pereira
Fábio
F
Regalo
Gonçalo
G
Figueiredo
Céu
C
Trindade
Eunice
E
Seruca
Raquel
R
Carneiro
Fátima
F
Amil
Jorge
J
Machado
José Carlos
JC
Tavarela-Veloso
Fernando
F
D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007223:Infant; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein; D011110:Polymorphism, Genetic / Q000235:genetics*; D011174:Portugal; D012795:Sialoglycoproteins / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha