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Association of IL23R Variants With Crohn's Disease in Korean Children.

ABSTRACT: Background: The interleukin 23 receptor gene (IL23R) is strongly associated with Crohn's disease (CD). It is unknown whether genetic variations in IL23R determine susceptibility for pediatric CD in Asian populations. Here, we investigated the association between IL23R variants and CD in Korean children. Methods: Four single nucleotide polymorphisms (SNPs) of IL23R [rs76418789 (G149R), rs1004819, rs7517847, and rs1495965] were genotyped in 141 children with CD and 150 controls using DNA direct sequencing. The risk allele and genotype frequencies were compared between patients and controls. The association between clinical phenotypes and genotypes of patients was also analyzed. Results: Two IL23R SNPs, rs76418789 (G149R), and rs1495965, were associated with CD in Korean pediatric patients as defense and risk loci, respectively. The odds ratio (OR) for rs76418789 (G149R) and rs1495965 was 0.409 (95% confidence interval [CI], 0.177-0.944; p = 0.031) and 1.484 (95% CI, 1.070-2.059; p = 0.018), respectively. Patients with the homozygous G allele of rs1495965 showed higher CD risk than those with other genotypes (GG vs. AA: OR, 2.256; 95% CI, 1.136-4.478; p = 0.019; GG vs. GA+AA: OR, 2.000; 95% CI, 1.175-3.404; p = 0.010). Additionally, they were more likely to have relatively invasive disease behavior of stenosis and/or penetration than simple inflammation (OR, 2.297; 95% CI, 1.065-4.950; p = 0.032). Conclusions: This is the first study reporting IL23R variants in Asian pediatric patients with CD. IL23R was significantly associated with Korean pediatric CD, and the rs1495965 may influence the clinical features of CD in Korean children.

SUBMITTER: Hong J

PROVIDER: S-EPMC6878822 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: The CTLA4 (cytotoxic T-lymphocyte antigen 4) gene is associated with several immunopathologic diseases and because of its important immuno-regulatory role it may be considered also a plausible candidate for a genetic association with inflammatory bowel diseases. Previously published studies found no association of CTLA4 with Crohn's disease itself, but some indicated an association with its subphenotypes. The aim of this study was to assess the association in the Czech population, using a set of markers shown to associate with other diseases. METHODS: Six polymorphisms within the CTLA4 region were investigated in 333 patients with Crohn's disease and 482 unrelated healthy controls, all Caucasians of Czech origin. The genotypes of the SNPs were determined using the TaqMan SNP genotyping assays. Haplotypes were reconstructed using an expectation-maximization algorithm, and their association with the condition was assessed using log-linear modeling. Then, potential interactions were tested between the CTLA4 variants and other genetic factors known to confer the disease susceptibility. RESULTS: No crude associations with Crohn's disease were found for the tested CTLA4 variants under the log-additive or dominant models. However, when stratified for the genetic risk conferred by the variants in the NOD2 (the p.Leu1007fsX1008, rs5743293) or the IL23R (p.R381Q, rs11209026), a significant negative association emerged for the minor alleles of CTLA4 CT60 (rs3087243), JO31 (rs11571302), JO27-1 (rs11571297) polymorphisms. This negative association with CTLA4 was apparent only in the strata defined by presence minor alleles at the NOD2 rs5743293 (here the CTLA4 CT60 A coffered an OR = 0.43, 95%CI 0.19 - 0.95 for the presence of CT60 A), or IL23R rs11209026 (here the OR for presence of CT60 A was 0.23, 95%CI 0.07 - 0.71). We observed this effect also for the haplotype consisting of minor alleles of the three tightly linked CTLA4 markers. Furthermore, this haplotype was associated with the younger age at diagnosis (OR 1.52, 95%CI 1.09 - 2.11, p = 0.014). CONCLUSIONS: A protective effect of a CTLA4 haplotype was unmasked after stratification for the risk variants in the NOD2 and IL23R genes, and may point towards the biological relevance of the molecule in the pathogenesis of the disease.

Project description:AIM:To assess whether the polymorphisms of NOD2/CARD15, autophagy-related 16-like 1 (ATG16L1), and interleukin-23 receptor (IL23R) genes play a more critical role in the susceptibility of childhood-onset than in adult-onset Crohn's disease (CD). METHODS:Polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15; rs2241880 A/G of ATG16L1, and rs11209026 (R381Q) of IL23R gene were assessed in 110 childhood-onset CD, 364 adult-onset CD, and 539 healthy individuals. Analysis of polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 genotyping was performed by allele specific polymerase chain reaction (PCR) or by PCR-restriction fragment length polymorphism analysis. The polymorphisms rs2241880 A/G of the ATG16L1, and rs11209026 (R381Q) of the IL23R gene in the children's cohort were genotyped by PCR and melting curve analysis whereas adult group genotyping was performed using the Affymetrix Genome-Wide Human SNP Array 5.0 (500K). RESULTS:The 3020insC allele in NOD2/CARD15 was significantly higher in childhood than in adult-onset CD (P = 0.0067). Association with at least 1 NOD2/CARD15 variant was specific for ileal disease (with or without colonic involvement). Even if the frequency of G allele of the rs2241880 ATG16L1 polymorphism was increased in both paediatric and adult CD patients compared to controls (P = 0.017 and P = 0.001, respectively), no difference was observed between the childhood and the adult cohort. The rare Q allele of IL23R rs11209026 polymorphism was underrepresented in both paediatric and adult CD cases (P = 0.0018 and P = 0.04, respectively) and no difference was observed between the childhood and the adult cohort. The presence of the rs2241880 ATG16L1 and rs11209026 IL23R polymorphisms did not influence disease phenotype. CONCLUSION:Polymorphism 3020insC in NOD2/CARD15 occurs statistically significantly more often in patients with childhood-onset CD than in patients with adult-onset CD. The ATG16L1 and IL23R variants are associated with susceptibility to CD, but not early-onset disease.

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Association of IL23R Variants With Crohn's Disease in Korean Children.

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