Background: Inflammatory bowel disease (IBD) has been associated with several polymorphisms in genes likely involved in innate immune responses and integrity of epithelial mucosal barrier. A major role in adult Crohn's disease (CD) has been defined for 3 polymorphisms in the CARD15 gene, whereas variants in the SLC22A4, SLC22A5, and DLG5 genes could have a minor contribution to IBD susceptibility.
Methods: We analyzed a panel of 6 polymorphisms within these genes in 227 Italian early-onset IBD patients (134 CD, 93 ulcerative colitis [UC]; age at diagnosis <or=18 years) and 166 unaffected control subjects.
Results: Each CARD15 variant was found to be independently associated with CD. After the genotypes at the 3 polymorphisms were combined, 37.3% patients carried at least 1 variant compared with 9.2% control subjects (odds ratio, 5.87; 95% CI 3.11-11.1; P < 0.001). The combined frequency of CARD15 variants was also higher in UC children compared with control subjects (14% vs 9.2%), but this difference was not significant. However, CARD15 variants were associated with earlier onset of UC, and the mutation rate was significantly higher in UC patients with onset at or before 6 years of age compared with control subjects (27.6% vs 9.2%) (odds ratio = 3.76; 95% CI 1.42-9.94; P = 0.01). CARD15 variants also were associated with ileal CD involvement and a higher rate of extraintestinal manifestations in UC. Allele and genotype frequencies at SLC22A and DLG5 polymorphisms were not significantly different between cases and controls.
Conclusions: Our results demonstrate that in the Italian population, the major CARD15 polymorphisms are associated with susceptibility to early-onset CD and with ileal involvement and suggest a previously unreported association with very early-onset, severe UC.