The association of ATG16L1 T300A with CD was confirmed [P = 0.004, odds ratio (OR) = 1.69, 95% CI: 1.19-2.41], and both IL23R variants were found to represent significant risk for the disease (P = 0.008, OR = 2.05, 95% CI: 1.20-3.50 for rs1004819 AA; P < 0.001, OR = 2.97, 95% CI: 1.65-5.33 for rs2201841 CC).
This study was aimed to investigate the possible association of Crohn's disease (CD) with inflammatory bowel disease gene 5 (IBD5) IGR2198a_1 (rs11739135), IGR2096a_1 (rs12521868) and interleukin-23 receptor (IL23R) genetic variant (rs1004819) in the Malaysian population.
IL23R is an IBD susceptibility gene, but has no epistatic interaction with CARD15 and SLC22A4/5. rs1004819 is the major IL23R variant associated with CD in the German population, while the p.Arg381Gln IL23R variant is a protective marker for CD and UC.
Two IL23R gene variants, an intronic SNP rs1004819 and intergenic SNP rs1495465, showed significant associations with CD; the adjusted odds ratio (aOR) for rs1004819 was 1.822 (95% confidence interval [CI] = 1.164-2.852, P = 0.009) and aOR for rs1495965 was 1.650 (95% CI = 1.102-2.471, P = 0.015).
Significant gene-gene interactions were also observed for the TLR9 polymorphism -1237T/C with IL23R variants (most significantly with rs1004819, P=0.0007), with a particular high frequency of -1237C in CD patients carrying CD-protective IL23R variants.
Multivariate analysis showed independent CD association for carriers of ATG16L1 (odds ratio [OR] = 1.8, 95% confidence interval [CI] 1.09-3.24), IBD5-IGR2230 (OR = 2.16, 95% CI 1.30-3.59), and IL23R-rs10889677 (OR = 2.13, 95% CI 1.39-3.28) while retaining association for NOD2 mutation carriers (OR = 4.45, 95% CI 2.68-7.38), IBD family history (OR = 2.75, 95% CI 1.42-5.31), tobacco (OR = 2.06, 95% CI 1.35-3.14), and Jewish ethnicity (OR = 20.1, 95% CI 2.16-186.8).
We observed an increased prevalence of the homozygous rs10889677 AA and homozygous rs2201841 CC genotypes both in the Crohn's disease and in the RA groups as compared to the controls (12.1%, 11.9% vs 5.91%, p<0.05; and 13.2%, 13.1% vs 5.91%, p<0.05), but not in the SSc patients.
Using regression analysis models the rs1004819, rs2201841, and rs10889677 SNPs were found to confer risk for Crohn's disease and ankylosing spondylitis, while rs1343151 had a protective effect in both of these diseases, and the rs2201841 and rs10889677 SNPs showed susceptibility nature for rheumatoid arthritis.
A subgroup analysis showed that the genetic models of rs10889677 polymorphism were associated with CD risk in Caucasians (p < 0.05), but not in Asians (p > 0.05).
IL23R is an IBD susceptibility gene, but has no epistatic interaction with CARD15 and SLC22A4/5. rs1004819 is the major IL23R variant associated with CD in the German population, while the p.Arg381Gln IL23R variant is a protective marker for CD and UC.
This data provides an explanation for the protective role of R381Q in CD and may lead to the development of improved therapeutics for autoimmune disorders like CD.