Association of IL23R polymorphisms with psoriasis and psoriatic arthritis: a meta-analysis

Background

The association of variants in the IL23R gene with psoriasis and psoriatic arthritis (PsA) is a robust genetic finding

Objectives

To assess whether combined evidence shows the association between IL23R polymorphisms and susceptibility to psoriasis/PsA.

Methods

We conducted a meta-analysis to examine the association between the IL23R rs11209026 (Q381R), rs7530511 (L310P), and rs2201841 polymorphisms and psoriasis/PsA.

Results

Thirteen articles met the inclusion criteria and contributed data to the meta-analysis. For rs11209026, the odds ratios (ORs) of minor alleles for psoriasis and PsA were 0.616 [95?% confidence interval (CI) 0.563–0.674] and 0.630 (95?% CI 0.524–0.757), respectively. For rs7530511, the pooled ORs were 0.820 (95?% CI 0.764–0.879) for psoriasis and 0.875 (95?% CI 0.766–1.000) for PsA; for rs2201841 the OR was 1.121 (95?% CI 1.031–1.219) for psoriasis. In genotypic analysis, the association of rs11209026 (A) and rs7530511 (T) were compatible with the dominant model (P?P?=?0.001 respectively). The overall ORs for GG vs. AA (OR 1.339; 95?% CI 1.151–1.558), GG vs. GA (OR 1.143; 95?% CI 1.004–1.300), dominant (OR 1.226; 95?% CI 1.143–1.316), and recessive (OR 1.254; 95?% CI 1.115–1.411) models of rs2201841 were all significantly increased in psoriasis. No publication bias was present.

Conclusions

Our results demonstrate a significant association between IL23R gene polymorphisms and psoriasis/PsA.     

Analysis of interleukin-23 receptor (IL23R) gene polymorphisms in systemic lupus erythematosus

The aim of this study was to evaluate the association between systemic lupus erythematosus (SLE) and polymorphisms in the interleukin-23 receptor (IL23R) gene, which have been previously found to be associated with two autoimmune diseases: inflammatory bowel disease and psoriasis. Our study includes 224 SLE patients and 342 healthy controls. The genotyping of IL23R variants was carried out using a polymerase chain reaction system with predeveloped TaqMan allelic discrimination assays. No statistically significant differences were observed between SLE patients and healthy controls with any of the IL23R genetic variants. In addition, we did not find any significant differences when we stratified SLE patients according to their clinical and demographic features. These results suggest that IL23R polymorphisms do not appear to play an important role in the susceptibility or severity of SLE in the Spanish population.     

Association of TNF,IL12, and IL23 gene polymorphisms and psoriatic arthritis: meta-analysis

Background: Psoriatic arthritis (PsA) is a chronic skin and joint condition that considerably affects patient quality of life. Several studies have demonstrated different associations of genetic polymorphisms in the pathogenic process of PsA. Therefore, we conducted a meta-analysis to estimate the effect of polymorphisms in the cytokines TNF, IL12B, IL23A, and IL23R on PsA risk.

Methods: We screened 1,097 abstracts and identified 14 relevant studies published between January 2007 and December 2017. A systematic search was conducted in PubMed, Web of Knowledge and Scopus databases. Meta-analyses were performed for the comparisons of alleles and multiple genetic models.

Results: Among the cytokines studied, we found 17 polymorphisms that were the most investigated. The association to PsA was observed in the presence of polymorphisms: TNF-238 G > A (rs361525), ?308 G > A (rs1800629), and ?857 C > T (rs1799724); IL12B C > G (rs6887695) and A > C (rs3212227); IL23A A > G (rs2066808) and IL23R G > A (rs11209026).

Conclusion: Our findings suggest that these variant cytokine genes may strongly influence the immunological response of PsA.     

Association of IL17 and IL23R gene polymorphisms with rheumatic heart disease in South Indian population

ABSTRACT

Background: IL-23/Th17 signaling pathway plays a crucial role in the cell-mediated immune response against bacterial infections and also in the pathogenesis of inflammatory and autoimmune diseases. Recent studies indicate that Th17 cell-associated cytokines are involved in the progression and maintenance of valvular lesions in rheumatic heart disease (RHD). Variants in the genes of cytokines that are potentially involved in Th17 response may influence interindividual differences in their expression levels, thereby contributing to the pathogenesis of immune-mediated diseases such as RHD.

Objective: The aim of the study is to investigate the association of IL17A, IL17F, and IL23R gene variants with the risk perception of RHD.

Methods: A total of 225 individuals (99 RHD patients and 126 healthy siblings) were recruited for the study. The IL17A (rs2275913), IL17F (rs763780), and IL23R (rs10889677) polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphisms and amplification-refractory mutation system-polymerase chain reaction methods, respectively.

Results: The frequency of IL17A (rs2275913) A/A genotype was significantly high in pooled RHD patients (odds ratio [OR] = 2.76; p_c = 0.021), rheumatic fever (RF) patients (OR = 14.5; p_c = 0.0001), and mitral valvular lesions patients (OR = 2.74; p_c = 0.039) when compared to healthy siblings. However, the IL17F (rs763780) and IL23R (rs10889677) polymorphisms did not show any association with RHD.

Conclusions: The results suggest that IL17A (rs2275913) polymorphism is associated with the development of RF/RHD in South Indian population. Further studies are required to substantiate the association of these genes with the disease risk.     

Investigation of CD69 as a new candidate gene for rheumatoid arthritis

The aim of this study was to investigate the CD69 gene as a new functional candidate gene for rheumatoid arthritis (RA) genetic predisposition. A case–control association study including 933 RA patients and 800 healthy individuals was conducted. Five haplotype-tagging single nucleotide polymorphisms (SNPs) (rs929615, rs3176806, rs4763299, rs11052877, and rs3176789) covering the CD69 gene coding, 5' and 3' untranslated regions were selected as CD69 genetic markers and genotyped using a Taqman 5' allelic discrimination assay. No statistically significant differences were observed in the single marker association study with regard to either genotypic or allelic frequencies when considering the rs929615, rs3176806, rs4763299, rs11052877, and rs3176789 CD69 SNPs independently. According to these findings, no statistically significant skewing was observed between the RA patients and the controls in the distribution of CD69 haplotypes. In summary, our results do not support a major role for the CD69 gene polymorphisms in RA genetic predisposition in our population.     

Evaluation of IL17A expression and of IL17A,IL17F and IL23R gene polymorphisms in Brazilian individuals with periodontitis

The IL23/Th17 axis plays an important role in the pathogenesis of cell-mediated tissue damage caused either by autoimmunity or immune responses against bacterial infection. Single nucleotide polymorphisms in the IL17A, IL17F and IL23R genes have been associated with several inflammatory diseases. However, these polymorphisms have not yet been studied in periodontitis. The aim of present study was to evaluate the expression of IL17A and occurrence of the IL17A (rs2275913), IL17F (rs763780) and IL23R (rs11209026) gene polymorphisms in different clinical forms or severity of periodontitis in a sample of Brazilian individuals. Peripheral blood was obtained from 30 non-smoker individuals and analyzed by flow cytometry to determine IL-17 expression. Genomic DNA was obtained from oral swabs in 180 individuals and analyzed by Real-time PCR. The study group was composed by individuals without periodontitis (control), with aggressive periodontitis (AP) and with chronic periodontitis (CP). Higher frequency of IL17A+CD4+ T cells was observed in control group. The A+ genotype from IL17A (rs2275913) was associated with lack of disease. No association was found considering the IL17F and IL23R polymorphisms. Our data suggest that IL17A and the presence of IL17A (rs2275913) A allele are associated with the absence of periodontal disease.     

Lack of association of IL6R rs2228145 and IL6ST/gp130 rs2228044 gene polymorphisms with cardiovascular disease in patients with rheumatoid arthritis

Interleukin-6 (IL-6) is a key mediator of inflammation in rheumatoid arthritis (RA) and its actions may be controlled by the IL-6 receptor (IL-6R). IL-6 transducer (IL-6ST/ gp130) is the signal transducing subunit of the IL-6R. We assessed the influence of the IL6R and the IL6ST/gp130 genes in the risk of cardiovascular (CV) disease in RA. For this purpose, 1250 Spanish patients with RA were genotyped for the IL6R rs2228145 and IL6ST/gp130 rs2228044 functional gene polymorphisms. Patients were stratified according to the presence or absence of CV events. Also, a subgroup of patients without CV events was assessed for the presence of subclinical atherosclerosis using two surrogate markers of atherosclerosis (flow-mediated endothelium-dependent vasodilatation and carotid intima-media thickness). No significant differences in the genotype and allele frequencies for both gene polymorphisms between patients with and without CV events were observed. It was also the case when values of surrogate markers of atherosclerosis were compared according to IL6R and IL6ST genotype frequencies. In conclusion, our results do not confirm an association of IL6R rs2228145 and IL6ST/gp130 rs2228044 polymorphisms with CV disease in RA.     

The autoimmune disease-associated IL12B and IL23R polymorphisms in multiple sclerosis

Recently published genetic studies in psoriasis, inflammatory bowel disease, and ankylosing spondylitis identified significant associations with IL12B and IL23R polymorphisms. An important role for the IL-12/IL-23 pathway in multiple sclerosis (MS) is supported by immunologic studies in patients and animal models. To determine whether IL12B/IL23R disease-associated polymorphisms play a role in susceptibility to MS, we genotyped 910 MS-nuclear families, totaling 3132 individuals. Family-based association analysis was performed. There was no evidence of transmission distortion of any of the tested alleles in this data set.     

CTLA4 polymorphisms in Spanish patients with rheumatoid arthritis

Cytotoxic T-lymphocyte antigen 4 (CTLA4) polymorphisms located in the promotor region at positions -318 (C/T) and in exon 1 (49 A/ G) were investigated in 138 Spanish patients (37 men and 101 women) with rheumatoid arthritis and in 305 ethnically-matched healthy controls. When the allelic and genotypic frequencies corresponding to the CTLA4 -318 position were compared, no significant differences between patients and controls were found. However, when the CTLA4 49 A/G polymorphism was analysed, a significant increase of A/G heterozygous individuals among female patients (48.5% vs. 33.8% in controls; P=0.008; OR=2.0) was observed. This increase was absent among males (37.8%, P=NS). Analysis of the CTLA4 49 polymorphism with respect to HLA-DRB1 typing demonstrated a significant increase of A/G heterozygosity in the HLA-DR3-positive patient group compared with HLA-DR3-negative patient group (14/19, 74% vs. 49/119, 41%; P=0.009, OR=4.0). The increase of A/G genotype among HLA-DR3-positive patients was found in both males (4/6, 67%) and females' (10/13, 77%), although statistical differences were only reached in the female group. These results provide new insight into this complex association, confirm previous data from other studies, and suggest that the CTLA4 gene could be involved in the pathogenesis of rheumatoid arthritis.     

An emerging role of interleukin-23 in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune, chronic inflammatory disease and is characterized by destruction of the articular cartilage. A number of pro-inflammatory cytokines work sequentially and in concert with one another to induce the development of RA. IL-23, a member of IL-12 family, is composed of p19 and p40 subunits and it interacts with IL-23 receptor complex to trigger plethora of biochemical actions. A number of preclinical studies have shown the role of IL-23 in the development of RA in rodents. IL-23 receptor signaling is primarily linked to the activation of JAK-STAT, tyrosine kinase 2, NF-kB, and retinoic acid receptor-related orphan receptors. IL-23 produces its osteoclastogenic effects, mainly through IL-17 and Th17 cells suggesting the importance of IL-23/IL-17/Th17 in the joint inflammation and destruction in RA. Monoclonal antibodies targeted against IL-23, including tildrakizumab and guselkumab have been developed and evaluated in clinical trials. However, there are very limited clinical studies regarding the use of IL-23 modulators in RA patients. The present review discusses the different aspects of IL-23 including its structural features, signal transduction pathway, preclinical, and clinical role in RA.     

IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis

The interleukin (IL)-17/IL-23 axis is an important pro-inflammatory pathway in rheumatoid arthritis (RA). IL-23 maintains CD4(+) T-helper 17 (Th(17)) cells, whereas IL-12 negates IL-17A production by promoting Th(1)-cell differentiation. We sought evidence for any effect of polymorphisms within the interleukin-23 receptor (IL-23R), IL-12 or IL-21 genes on serum cytokine concentrations in 81 patients with RA. Serum cytokines were measured using bead-based multiplex assays. Targeted cytokines were detected in up to 66% of samples. A subgroup of 48 patients had detectable serum IL-17A. Within this subgroup, patients, homozygous for the IL-23R rs11209026 major allele had significantly higher serum IL-17A concentrations compared with patients with the minor allele (394.51 ± 529.72 pg ml(-1) vs 176.11 ± 277.32 pg ml(-1); P = 0.017). There was no significant difference in any of the cytokine concentrations examined in patients positive for the minor allele vs homozygosity for the major allele of IL-12B rs3213337, IL-12Bpro rs17860508 and IL-21 rs6822844. Our results suggest the IL-23R Arg381Gln substitution may influence serum IL-17A concentrations. In patients with the 381Gln allele higher IL-23 concentrations may be needed to produce similar IL-17A concentrations to those in patients with the 381Arg allele. This suggests altered IL-23R function in patients with the minor allele and warrants further functional studies.     

Evidence of association of interleukin-23 receptor gene polymorphisms with Egyptian rheumatoid arthritis patients

BackgroundThe identification of additional genetic risk factor is an on-going process that will aid in the understanding of rheumatoid arthritis (RA) aetiology. A genome-wide association scan in Crohn’s (CD) disease highlighted the interleukin-23 receptor (IL23R) gene as a susceptibility factor. Since the IL-23/IL-17 pathway is known to associate with other autoimmune disease, including rheumatoid arthritis and systemic sclerosis, we hypothesised that IL23R could be a shared susceptibility gene. The rare allele of IL23R single nucleotide polymorphism (SNP) rs11209026 (Arg381Gln) confers strong protection against CD. Our aim was to analyse IL23R SNP (rs11209026, rs2201841, and rs10889677) and to detect its association with RA in Egyptian patients.MethodsA group of Egyptian patients with RA (n = 120) and apparently healthy persons as controls (n = 120) was genotyped for rs11209026, rs2201841 and rs10889677 by real time/polymerase chain reaction (real-time/PCR) for the first SNP and restriction fragment length polymorphism/PCR (RFLP/PCR) in the last two SNPs.ResultsOur data emphasise that the AA genotype of rs11209026 (Arg381Gln) was significantly associated with RA patients compared to the controls (P value = 0.001).We did not find any significant association between either rs2201841 or rs10889677 and the development of rheumatoid arthritis (P value = 1.000 & 0.562 respectively).ConclusionOur results suggest that IL23 receptor AA genotype variant of rs11209026 would contribute to RA aetiology; consequently, it might be a genetic marker for RA. We need to address the subgroup of patients who will benefit from the selective suppression of the IL23 signalling which would represent new perspectives toward a personalized therapy of RA patients by further studies.     

Interleukin 12 (IL12B) and interleukin 12 receptor (IL12RB1) gene polymorphisms in rheumatoid arthritis

The aim of this study was to assess the possible association between the IL12B and the IL12RB1 gene polymorphisms and the systemic autoimmune disease rheumatoid arthritis (RA). Our study population consisted of 545 patients with RA and 393 healthy subjects. All the individuals were of white Spanish origin. Genotyping of the IL12B (IL12Bpro and IL12B 3' untranslated region) and IL12RB1 (641A-->G, 1094T-->C, and 1132G-->C) polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism and polymerase chain reaction-fluorescent methods. No statistically significant differences in the distribution of the IL12B and the IL12RB1 genotypes and alleles between patients with RA and control subjects were observed. In addition, no association was found between the above-mentioned polymorphisms with any of the demographic and clinical parameters tested in patients with RA. These results suggest that IL12B and IL12RB1 genes may not play a relevant role in the susceptibility or severity of RA in the Spanish population.     

MCP-1 promoter polymorphism in Spanish patients with rheumatoid arthritis

To investigate the possible role of the polymorphism located in the regulatory region of monocyte chemoattractant protein-1 (MCP-1) gene in the susceptibility to rheumatoid arthritis (RA), a total of 141 Spanish RA patients and 194 controls, previously typed for human leukocyte antigen DRB1* (HLA-DRB1*), were genotyped for -2518 (A/G) MCP-1 gene polymorphism using polymerase chain reaction-restriction fragment length polymorphism. No association between -2518 (A/G) MCP-1 polymorphism and susceptibility to RA was found. Nevertheless, when patients and controls were stratified according to their HLA shared epitope (SE) status, a significant increase in the frequency of genotype GG was found among SE negative (SE-) patients with respect to both SE positive (SE+) patients and SE- controls (16% versus 4% in SE+ patients, pFisher=0.04, odds ratio [OR]=4.4, 95% confidence interval [95%CI]=1.03-21.48; and 4% in SE- controls, pFisher=0.02, OR=4.13, 95%CI=1.10-15.72). In conclusion, MCP-1 polymorphism is slightly associated with the susceptibility to RA in patients lacking the HLA SE.     

No evidence of association of the KLF12 gene with rheumatoid arthritis in Spanish and Dutch cohorts and a meta-analysis of published data

The aim of the present study was to replicate the previously reported association of KLF12 gene polymorphisms with rheumatoid arthritis (RA). Two independent cohorts from Spain (1,360 RA patients and 1,520 controls) and the Netherlands (1,018 RA patients and 1,150 controls) were genotyped for KLF12 rs1887346 and rs9565072 single-nucleotide polymorphisms using a TaqMan 5'-allele discrimination assay. No evidence of association of RA with the minor T allele of rs9565072 (31.82% vs 33.73%; p = 0.14, odds ratios [OR] 0.92 [95% confidence interval (CI) 0.82-1.03]) or the minor A allele of rs1887346 polymorphism (21.60% vs 21.77%; p = 0.88, OR 0.99 [95% CI 0.87-1.13]) was observed in Spanish patients compared with healthy controls. This lack of association was also confirmed in the Dutch cohort: the minor T allele frequency of rs9565072 in Dutch RA patients was 35.34% versus 35.57% in controls; p = 0.87, OR 0.99 (95% CI 0.87-1.12); and the minor A allele frequency of rs1887346 in Dutch RA patients was 27.64% versus 28.17% in controls; p = 0.70, OR 0.97 (95% CI 0.85-1.12). A meta-analysis of published KLF12 gene association with RA revealed a pooled OR of 0.99 (95% CI 0.93-1.04) for rs1887346 and a pooled OR of 0.99 (95% CI 0.95-1.04) for rs9565072. In conclusion, our findings indicate that the KLF12 rs1887346 and rs9565072 polymorphisms do not play a relevant role in RA.     

IL‐23R gene polymorphism rs2201841 is associated with psoriatic arthritis

We examined rs2201841 within IL‐23R gene in Serbian patients with psoriasis and healthy controls. G allele frequency was significantly increased in the group of patients with psoriatic arthritis compared with controls (0.481 vs 0.308). Carriage of G allele increases risk to develop psoriatic arthritis (P = 0.009, OR = 3.311, 95% CI 1.29–8.70).     

类风湿关节炎患者单个核细胞IL-23的表达及意义

目的:通过分析比较类风湿关节炎(Rheumatoid Arthritis,RA)患者血清和外周血单个核细胞(Peripheral bloodmononuclear cell,PBMC)IL-23的表达,探讨其在RA发病过程中的作用,以期为治疗开辟新途径。方法:应用ELISA方法检测RA、骨性关节炎(Osteoarthritis,OA)及正常对照组血清中IL-23和TNFα-蛋白水平,采用RT-PCR法测定各组PBMC中IL-23p19mRNA的表达,并作血清IL-23含量、PBMC IL-23p19mRNA的表达与血清TNFα-水平的相关分析。结果:RA组血清IL-23水平高于正常对照组(P=0.001),其他组间无统计学差异(分别为P=0.122,P=0.127);而各组血清TNFα-的水平均具有统计学差异,RA和OA组均高于对照组(P=0.000,P=0.042),RA组也高于OA组(P=0.013);RA组IL-23p19mRNA的表达高于OA和正常对照组(P=0.000,P=0.000),而OA组与正常对照组差异无统计学意义(P=0.628);血清中IL-23和TNFα-的相关性无统计学差异(r=0.212,P=0.262),而PBMC中IL-23p19mRNA的表达与血清TNFα-呈正相关关系(r=0.392,P=0.032)。结论:IL-23在RA患者PBMC中高表达,在RA的炎性发展过程起到了重要作用。