Abstract
BackgroundThe IL23R gene has been identified as a susceptibility gene for inflammatory bowel disease (IBD) in the North American population. The aim of our study was to test this association in a large German IBD cohort and to elucidate potential interactions with other IBD genes as well as phenotypic consequences of IL23R variants.MethodsGenomic DNA from 2670 Caucasian individuals including 833 patients with Crohn's disease (CD), 456 patients with ulcerative colitis (UC), and 1381 healthy unrelated controls was analyzed for 10 IL23R SNPs. Genotyping included the NOD2 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008 and polymorphisms in SLC22A4/OCTN1 (1672 C→T) and SLC22A5/OCTN2 (–207 G→C).ResultsAll IL23R gene variants analyzed displayed highly significant associations with CD. The strongest association was found for the SNP rs1004819 [P = 1.92×10−11; OR 1.56; 95 % CI (1.37–1.78)]. 93.2% of the rs1004819 TT homozygous carriers as compared to 78% of CC wildtype carriers had ileal involvement [P = 0.004; OR 4.24; CI (1.46–12.34)]. The coding SNP rs11209026 (p.Arg381Gln) was protective for CD [P = 8.04×10−8; OR 0.43; CI (0.31–0.59)]. Similar, but weaker associations were found in UC. There was no evidence for epistasis between the IL23R gene and the CD susceptibility genes CARD15 and SLC22A4/5.Conclusion 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.
Highlights
Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract characterized by a perpetuated mucosal immune response which is triggered by intestinal bacteria in genetically susceptible individuals [1,2]
In all three subgroups (CD, UC, and controls), the genotype frequencies of the 10 IL23R single nucleotide polymorphisms (SNPs) were in accordance with the Hardy-Weinberg equilibrium
The present study confirms the previously described association of IL23R gene variants with CD in a large German inflammatory bowel disease (IBD) patient cohort and demonstrates a particular role for the rs1004819 variant in the pathogenesis of CD in German patients. It is the first study analyzing for potential epistasis between IL23R variants and the three other previously described CD susceptibility genes CARD15, SLC22A4, and SLC22A5
Summary
Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract characterized by a perpetuated mucosal immune response which is triggered by intestinal bacteria in genetically susceptible individuals [1,2]. Duerr et al [12] identified the IL23R gene located on chromosome 1p31 as an IBD susceptibility gene in a genome-wide association study testing 308,332 single nucleotide polymorphisms (SNPs) in non-Jewish ileal CD cases and controls. The uncommon IL23R coding variant rs11209026 (1142G.A; p.Arg381Gln) was associated with strong protection against CD [12]. This was recently confirmed in a British cohort [13] and for pediatric CD [14,15]. For nine other variants located within the IL23R gene or in the intergenic area with the adjacent IL12RB2 gene, Duerr et al [12] demonstrated associations with CD with p-values of ,0.0001. 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
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