IL23RandIL12BSNPs and Haplotypes Strongly Associate with Crohn's Disease Risk in a New Zealand Population

Abstract

DNA samples from 339 Crohn's disease (CD) and 407 randomly selected controls from the Auckland (New Zealand) IBD project, were genotyped for five common single nucleotide polymorphisms in IL-23R (rs11805303, rs7517847, rs1343151, rs11209026, and rs10889677) and two in IL-12B (rs1363670 and rs6887695). While the IL-12B variants did not show an overall association and other IL23R variants led to minor changes in the risk of CD, rs1343151 and/or rs7517847 variants in the IL-23R gene strongly reduced the risk of developing CD at both allelic and genotype levels. A significantly decreased risk of first diagnosis of childhood CD was observed in individuals carrying the A allele of rs1343151, or between 17–40 y in individuals carrying the G allele in rs7517847 of IL-23R. A significantly decreased risk of ileocolonic or structuring disease was observed in individuals carrying the A allele in either rs11209026 or rs1343151, or the G allele in rs7517847 of IL-23R, and when such individuals did develop the disease, they were unlikely to require a bowel resection. Certain haplotypes very strongly modified risk. There was evidence for interactions of IL-23R variants with the NOD2 wild-type (d/d) genotype. Down-regulating the function of the IL-23R gene may decrease CD risk in the normal population.

Protective role of R381Q (rs11209026) polymorphism in IL-23R gene in immune-mediated diseases: A comprehensive review

“…In humans, IL-23 is over-expressed in clinical samples of psoriasis (Lee et al 2004), CD (Schmidt et al 2005) and ankylosing spondylitis (Wang et al 2009). Becker et al (2006) showed that blocking the p40 subunit of either IL-12 or IL-23, but not blocking the p19 unit (Ferguson et al 2010), was effective in reducing disease symptoms in chemically-induced colitis models. They suggested that there is a pre-disposition to IL-23-induced chronic inflammation in the terminal ileum.…”

“…The frequency of a functional single nucleotide polymorphism (SNP) in the IL-23 receptor gene (IL-23R; rs11209026, 1142 G wild-type A reduced function, Arg381Gln, R381Q) is significantly higher among healthy controls than in patients, suggesting a protective effect of the rare allele from immune-mediated chronic inflammation. The SNP rs11209026 encodes an amino acid change (Arg381Gln) in the protein product and has functional consequences; thus, R381Q is a causal variant (Ferguson et al 2010). This variant is a noncoding variant together with other genetic markers located in the IL23R gene (in exon 9 and coding for IL23R intra-cytoplasmic tail) and in its downstream intergenic region was identified as exerting a potent protective effect against IBD susceptibility.…”

“…However, the rs10889677 and rs2201841 in that study had no significant relationship with UC susceptibility. Ferguson et al (2010) detected five common SNP in the IL-23R gene (e.g. rs11805303, rs7517847, rs1343151, rs11209026, rs10889677) in CD patients from a New Zealand population and found that rs1343151 and/or rs7517847 variants strongly reduced the risk of developing CD at both the allelic and genotype level.…”

“…The statistical interaction for CD-associated variants in NOD2 with IL-12B and IL-23R was also investigated. The three NOD2 SNPs (rs2066844, rs2066845 and rs2066847) were classified as homozygous wild-type (d/d), heterozygous carrier (d/D) or homozygous mutant carrier, including compound heterozygotes (D/D), as previously identified in Ferguson et al (2010).…”

Replication of Identified Inflammatory Bowel Diseases Genetic Associations: A Case–Control Study in the Tunisian Population

“…This SNP was already reported to be associated with the susceptibility for CD and to be associated with ileal location in New Zealand population [44]. Multiple SNPs showing an association with both CD and UC have been identified in the IL23R gene by recent GWA studies.…”