IL23R Single Nucleotide Polymorphisms Research Articles

Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population

The results of a recent genome-wide association study have shown that ERAP1 and IL23R are associated with ankylosing spondylitis (AS) in Caucasian populations from North America and the UK. Based on these findings, we undertook the current study to investigate whether single-nucleotide polymorphisms (SNPs) covering the genes ERAP1 and IL23R are associated with AS in a Han Chinese population. A case-control study was performed in Han Chinese patients with AS (n = 527) and controls (n = 945) from Shanghai and Nanjing. All patients met the modified New York criteria for AS. The Sequenom iPlex platform was used to genotype cases and controls for 21 tag SNPs covering IL23R and 38 tag SNPs covering ERAP1. Statistical analysis was performed using the Cochran-Armitage test for trend. Multiple SNPs in ERAP1 were significantly associated with AS (for rs27980, P = 0.0048; for rs7711564, P = 0.0081). However, no association was observed between IL23R and AS (for all SNPs, P > 0.1). The nonsynonymous SNP in IL23R, rs11209026, widely thought to be the primary AS-associated SNP in IL23R in Europeans, was found not to be polymorphic in Chinese. Our results demonstrate that genetic polymorphisms in ERAP1 are associated with AS in Han Chinese, suggesting a common pathogenic mechanism for the disease in Chinese and Caucasian populations, and that IL23R is not associated with AS in Chinese, indicating a difference in the mechanism of disease pathogenesis between Chinese and Caucasian populations. This may result from the fact that rs11209026, the nonsynonymous SNP in IL23R, is not polymorphic in Chinese patients, providing further evidence that rs11209026 is the key polymorphism associated with AS (and likely inflammatory bowel disease and psoriasis) in this gene.

IL-23R Polymorphisms in Patients with Ankylosing Spondylitis in Korea: Table 1.

IL23R polymorphisms have been shown to have a significant association with ankylosing spondylitis (AS). To date, these studies have been restricted to Caucasian patients with AS. Our study addresses this relationship in Korean patients with AS. A total of 451 patients with AS and 392 ethnically matched healthy controls were enrolled. All patients were native Koreans with AS satisfying the modified New York criteria. In total, 10 single nucleotide polymorphisms (SNP) within the IL-23R gene cluster were genotyped. No IL-23R SNP were found to be associated with AS in Koreans. The association of IL23R and AS that is seen in Caucasian patients with AS is not present in Korean patients with AS.

Contribution of IL23R but not ATG16L1 to Crohnʼs disease susceptibility in Koreans

Recent genome-wide association studies in Caucasian populations identified IL23R and ATG16L1 as susceptibility genes to Crohn's disease (CD). We tested 5 IL23R single nucleotide polymorphisms (SNPs) and 12 ATG16L1 SNPs in Korean patients to determine whether these genes are associated with susceptibility to CD in a non-Caucasian population. We analyzed 5 IL23R SNPs and 12 ATG16L1 SNPs in 380 patients with CD and 380 healthy controls. 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). The genotype-phenotype analysis showed subphenotype specificity to stricturing and penetrating behaviors. On the other hand, none of the 12 ATG16L1 SNPs showed any positive association with CD in Koreans. The contribution of IL23R variants in Korean CD patients overall is low in comparison with studies of Caucasian. Our data in Koreans support the previous Caucasian reports of an association of the IL23R gene with CD.

Investigation of association of the IL12B and IL23R genes with psoriatic arthritis.

ObjectiveRecent reports have confirmed association of single-nucleotide polymorphisms (SNPs) mapping to the interleukin-23 receptor (IL-23R) and IL-12β genes with psoriasis susceptibility. The aim of this study was to determine whether these variants are also associated with susceptibility to psoriatic arthritis (PsA).MethodsTwo IL23R SNPs (rs7530511 and rs11209026) and 2 IL12B SNPs (rs3212227 and rs6887695) were genotyped in DNA samples from 520 white patients with PsA and 2,260 control subjects, all of whom resided in the UK. For SNP rs3212227, data on a larger group of controls (n = 4,681) were publicly available; this information was used in the analysis. Genotype counts were compared between patients with PsA and population controls, using the trend test.ResultsA haplotype comprising carriage of the common variants of both IL23R SNPs was associated with PsA susceptibility (adjusted P = 0.013 [1,000 permutations]). Both IL12B SNPs were independently associated with PsA susceptibility, and this association was strongest under a dominant model, with homozygosity for the common allele being more frequent in patients with PsA than in control subjects: for rs3212227, the odds ratio (OR) for carriage of AA versus other genotypes was 1.43 (95% confidence interval [95% CI] 1.17–1.76); for rs6887695, the OR for carriage of GG versus other genotypes was 1.43 (95% CI 1.18–1.74).ConclusionVariation within IL23R and IL12B is associated with susceptibility to both psoriasis and PsA. The effect sizes observed in patients with PsA appear to be smaller than those previously reported in patients with psoriasis, suggesting that both loci are primarily associated with psoriasis susceptibility. However, this does support the idea that the genetic etiology of the psoriasis present in patients with PsA has susceptibility loci in common with those observed in patients with uncomplicated psoriasis.

The Impact of NOD2/CARD15, TLR and IL23R Polymorphisms on the Incidence of Infectious Complications in Allo-HSCT Recipients.

BACKGROUND: Infections and graft-vs.-host disease (GvHD) remain the major obstacles for successful allogeneic stem cell transplantation (alloHSCT). As specific immune response is profoundly suppressed during the first months after transplantation, the components of innate immunity are expected to play important role in protection against infections and modulation of GvHD. The goal of this prospective study was to evaluate the impact of NOD2/CARD15 gene, toll-like receptors (TLR), and interleukin-23 receptor (IL-23R) single nucleotide polymorphisms (SNPs), on outcome of alloHSCT, including the incidence of infectious complications and acute GvHD. All these factors were documented to take part in innate immunity.PATIENTS: One-hundred-twenty-five consecutive patients, mainly with hematological malignancies, aged 32 (18–58)y, treated with alloHSCT from HLA-matched related (n=43) or matched unrelated donor (MUD) (n=82) were analyzed. The conditioning regimen was myeloablative, GVHD prophylaxis consisted of cyclosporin, metotrexate, and, in case of MUD-HSCT, pre-transplant anti-thymocyte globulin.METHODS: Donors and recipients were tested for SNP8,12,13 of the NOD2/CARD15 gene, TLR2/753, TLR4/299, TLR4/399, TLR5/C1174T, and TLR9/1635 SNPs, as well as IL23R/11209026 SNP. Study end-points included the incidence of bacterial, fungal and clinically relevant viral infections. Infections were recognized based on clinical symptoms, microbial cultures, chest X-rays for pneumonia confirmation and in case of CMV and EBV- PCR screening. We analyzed separately infections occurring in the early, cytopenic phase and those occurring after engraftment. Additionally, the incidence of acute GvHD and survival was evaluated.RESULTS: Presence of NOD2/CARD15 SNP8 in recipient resulted in higher frequency of neutropenic pneumonia (40% vs. 6%, p=0.045) and bacterial pharyngitis (100% vs. 50%, p=0.06), as well as increased incidence of grade III-IV acute GVHD (40% vs. 7%, p=0.05), which translated into increased non-relapse mortality (60% vs. 14%, p=0.005) and decreased 2-year overall survival (20% vs. 71%, p=0.003). TLR4/299 SNP in recipient tended to increase the risk of neutropenic fever (FUO) (67% vs. 30%, p=0.06) and decrease survival (71% vs. 48%, p=0.09). TLR2/753 SNP in donor was associated with higher incidence of FUO (83% vs. 30%, p-0.01), while TLR5/C1174T SNP in recipient resulted in increased incidence of EBV infection (25% vs. 4%, p-0.05). Presence of IL23R/11209026 SNP in donor tended to increase the incidence of neutropenic pneumonias (29% vs. 6%, p=0.09).CONCLUSIONS: NOD2/CARD15, TLR, and IL23R SNPs appear to influence outcome of alloHSCT contributing to increased incidence of infections, and in case of NOD2/CARD15 SNP8 in recipient to increased risk of severe acute GVHD. The genomic analysis may allow elaboration of adequate preventive strategies based on individual risk assessment. Our results encourage for further, extended studies.

Contributions of IBD5, IL23R, ATG16L1, and NOD2 to Crohnʼs disease risk in a population-based case-control study: Evidence of gene–gene interactions

IBD5, IL23R, and ATG16L1 genetic variations are established Crohn's disease (CD) risks alleles. We evaluated these in a population-based case-control study within a cohort to determine their penetrance, population attributable risk, independence, and relationship to other established CD risk factors, including NOD2. DNA from 213 CD, 118 [corrected] ulcerative colitis, and 315 [corrected] healthy control subjects from the population based University of Manitoba IBD Research Registry were genotyped for IBD5 and IL23R single-nucleotide polymorphisms (SNPs),and for the Thr 300Ala ATG16L1 SNP. Univariate and multivariate analyses were performed for these and nongenetic risk factors.We introduce multidimensionality reduction (MDR) to explore gene– gene interactions. ATG16L1, IBD5, and IL23R SNPs were significantly associated with CD. 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). IL23R minor variants for Arg381Gln and Intron 6 rs7517848 showed independent, CD protection and 3' untranslated variant rs108896778 showed risk. MDR analysis suggested an interaction between IBD5, ATG16L1, and IL23R risk alleles. Penetrance values for ATG16L1 and IBD5 were 0.27% for heterozygotes, and 0.35% and 0.44%, respectively, for homozygotes. IL23R rs108896778 penetrance was 0.37%. A population-based analysis of CD risk factors is useful for characterizing the epidemiology of multiple CD genetic and nongenetic risk factors. Gene-gene interactions are likely, but require further evaluation in large population-based cohorts.

IL23R and IL12B polymorphisms in spanish IBD patients: No evidence of interaction

Recent genomic surveys have identified IL23R and IL12B as susceptibility loci for inflammatory bowel disease (IBD). Our aim in the present study was to ascertain whether the IL23R and IL12B associations with IBD are also observed in our population, and to analyze possible genetic interactions between polymorphisms at IL12B and IL23R, ligand and receptor, respectively. In all, 707 IBD patients (344 with Crohn's disease and 363 with ulcerative colitis) and 547 healthy controls from the same ethnic origin (Caucasian Spaniards) were included in the present study. Two single nucleotide polymorphisms (SNPs) in IL23R (rs7517847 and rs11209026) and 2 in IL12B (rs3212227 and rs6887695) genes were analyzed by TaqMan technology. Genetic frequencies were compared with a chi-square test. Interaction between genes was analyzed by case-only comparisons. The data show an association of both IL23R SNPs with overall IBD (statistically stronger, rs7517847; odds ratio [OR] = 0.79, 95% confidence interval [CI]: 0.67-0.94, minor allele frequencies: 0.355 in IBD patients versus 0.410 in controls; P = 0.005), somewhat stronger in Crohn's disease (OR = 0.74, 95% CI: 0.61-0.91) than in ulcerative colitis (OR = 0.84, 95% CI: 0.69-1.03). IL12B rs6887695 showed a weak association with IBD (OR = 1.24, 95% CI: 1.04-1.47, minor allele frequencies: 0.375 in IBD patients versus 0.326 in controls, P = 0.012), stronger in UC (OR = 1.31, 95% CI: 1.07-1.60, P = 0.007). No statistically significant differences were apparent when patients were stratified according to clinical characteristics. No interaction was observed between any of the polymorphisms studied at IL12B and IL23R. Our study confirms the association of IL23R and IL12B with IBD in the Spanish population, but no interaction between either loci could be detected.

Linking genetic susceptibility to Crohnʼs disease with Th17 cell function: IL-22 serum levels are increased in Crohnʼs disease and correlate with disease activity and IL23R genotype status

We analyzed the influence of Crohn's disease (CD)-associated IL23R gene variants on IL-22 that is expressed in IL-23R+ Th17 cells. IL-22 serum levels were measured in 242 CD patients and in 31 healthy controls. Subanalyses included serum levels of IL-6, TNF-alpha, IL-17A, IL-17F, C-reactive protein (CRP), and leukocyte count. In all patients, genotyping for 10 CD-associated IL23R single nucleotide polymorphisms (SNPs) and the 3 main CD-associated CARD15 variants was performed. There was a highly significant increase in IL-22 serum expression in CD patients compared to healthy controls (P = 2.53 x 10(-9)). IL-22 serum levels correlated with disease activity: IL-22 levels in patients with a Crohn's disease activity index (CDAI) >150 were significantly higher than in patients with a CDAI <150 (P = 0.001), while TNF-alpha and IL-6 were not significantly different between these 2 groups. Analyzing the effect of 10 IL23R variants on IL-22 serum levels, we demonstrated that the quotients of mean IL-22 serum levels of carriers of the minor allele to the mean serum IL-22 in wildtype carriers correlated highly with the corresponding CD susceptibility risk for each gene variant (r = 0.807). The IL-22 levels in carriers of CD risk-increasing IL23R variants were significantly higher than in carriers of CD risk-decreasing IL23R variants (P = 0.008). The Th17 cytokine IL-22 is expressed at high levels in CD and correlates with disease activity, offering a better separation between active and inactive CD than IL-6 and TNF-alpha. IL23R genotypes influence IL-22 serum expression, linking genetic CD susceptibility to Th17 cell function for the first time.