In this study, ileal disease was also associated with the presence of at least one NOD2 susceptibility allele (p=0.001; OR=3.838) and, the risk of ileal CD was increased if TLR4 variants were presents (p<0.050; OR=4.160).
NOD2 mutations were highly associated with CD and stricturing behavior (P < .0001), with the p.1007fs mutation also conferring a risk for isolated ileal disease (P = .003).
CARD15 gene variants have been identified as a major genetic risk factor for CD patients and associated with ileal disease, stenosis, and risk of surgery.
After correction for age and smoking, CARD15 mutations were strongly associated with both ileal disease (P=8.8 x 10(-6)) and stenotic disease (P=0.003), but the association with stenotic disease appeared to be due to a confounding effect with ileal disease.
However, in the multivariate analysis for stricturing disease applying a non-hierarchical criteria, ileal disease (OR, 4.19; 95% CI: 1.30-13.5; P = 0.01), and carrying both NOD2/CARD15 variants and the 4G/4G PAI-1 genotype (OR, 5.02; 95% CI: 1.44-17.48; P = 0.01) were independent predictive factors.
The ASCA titer (odds ratio (OR): 2.7 per 25 U, 95% confidence interval (CI): 1.5-46.7) and ileal disease were associated with stricturing/penetrating behavior, independently of NOD2/CARD15 status.
NOD2/CARD15 variant frequency in ileal disease did not differ significantly among studies, whereas a comparison of disease location demonstrated highly significant differences among studies.
Genotype-phenotype analysis demonstrated that CARD15 variants were associated with ileal disease (p=0.0006, OR = 9.3, CI = 2.2-34) and protective for colonic CD (p = 0.01, OR = 0.18).
These results confirm that variant NOD2/CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease, stricturing disease behavior in Hungarian CD patients.
These results confirm that variant NOD2/CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease, stricturing disease behavior in Hungarian CD patients.
The association of the SLC22A -TC haplotype and CARD15 alleles with ileal disease suggests that these variants have biologically intertwined effects in the pathogenesis of CD.
NOD2/CARD15 was associated with ileal involvement, while presence of TNF-863A was inversely associated with ileal disease (OR = 0.42, p= 0.008) and positively associated with isolated colitis (OR = 2.16, p= 0.008, OR = 2.12, p= 0.03 corrected) and familial disease (p= 0.004).
We show a significant association of ileal involvement with CARD15 variants (OR = 1.8; p = 0.02), HLA-DRB1*0701 (OR = 1.9; p = 0.006) and DRB1*04 (OR = 1.7; p = 0.02) alleles and demonstrate the capacity of combined CARD15 and HLA-DRB1 genotyping to predict ileal disease in CD patients.
In a Spanish population from Madrid, mutations of the NOD2/CARD15 gene were a marker of susceptibility to Crohn disease and were associated with ileal disease.
These results suggest a role for NOD2 in the regulation of Paneth cell mediated responses against intestinal bacteria and a plausible mechanism to explain the selective association of NOD2 mutations with ileal disease.