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Sarangi S, Barik D, Nahak SK, Panda AK. Association of Interleukin 23 Receptor Polymorphisms with Predisposition to Rheumatoid Arthritis: An Updated Meta and Trial Sequential Analysis. Biochem Genet 2024; 62:4067-4086. [PMID: 38270697 DOI: 10.1007/s10528-023-10644-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 12/18/2023] [Indexed: 01/26/2024]
Abstract
The etiology of Rheumatoid Arthritis (RA) development remained unclear, and several factors, such as environmental, genetic, and immune system dysfunction, have been attributed to the susceptibility. Interleukin 23 (IL23) induces expansion of the Th17 cells through the IL-23 receptor (IL-23R) and believes in playing a major role in RA pathogenesis. Various genetic mutants in the IL23R gene (rs10489629, rs1343151, rs2201841, rs7517847, rs1004819, rs10889677, rs11209026, rs7530511) have been associated with the susceptibility RA, but results are contradictories. We performed a meta-analysis to establish the association of IL23R polymorphisms with susceptibility RA. For the meta-analysis, a detailed search of databases like Google Scholar, PubMed, Scopus, Web of Science, and Science Direct was conducted, and data were extracted from the included reports. The meta-analysis was performed by the Comprehensive Meta-Analysis v3 software. A significant association of IL-23R rs11209026 (AA vs. GG: Odds ratio = 2.250, p-value = 0.01; AA vs. GG+GA: Odds ratio = 2.271, p-value = 0.01), rs1343151 (A vs. G: Odds ratio = 1.091, p-value = 0.001; AA vs. GG: Odds ratio = 1.209, p-value = 0.001; GA vs. GG: Odds ratio = 1.116, p-value = 0.004; AA+GA vs. GG: Odds ratio = 1.135, p-value = 0.000; AA vs. GG+GA: Odds ratio = 1.144, p-value = 0.012) and rs10889677 (CA vs. CC: Odds ratio = 1.375, p-value = 0.041) polymorphisms were observed with increased susceptibility for the development of RA. In contrast, IL-23R rs10489629 (G vs. A: odds ratio = 0.901, p-value = 0.047, GG vs. AA: Odds ratio = 0.763, p-value = 0.022, GG vs. AA+AG: Odds ratio = 0.852, p-value = 0.00) and IL23R rs2201841 (CC vs. TT+TC: Odds ratio = 0.826, p-value = 0.026) variants were linked with protection against the development of RA. In addition, the trial sequential analysis revealed the inclusion of a sufficient number of studies in the present meta-analysis, and no further additional studies are required. IL-23R variants are associated with genetic susceptibility or resistance against the development of RA.
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Affiliation(s)
- Surjyapratap Sarangi
- ImmGen EvSys Lab, Department of Biotechnology, Berhampur University, Bhanja Bihar, Berhampur, Odisha, 760007, India
| | - Debashis Barik
- ImmGen EvSys Lab, Department of Biotechnology, Berhampur University, Bhanja Bihar, Berhampur, Odisha, 760007, India
| | - Suraj Kumar Nahak
- ImmGen EvSys Lab, Department of Biotechnology, Berhampur University, Bhanja Bihar, Berhampur, Odisha, 760007, India
| | - Aditya K Panda
- ImmGen EvSys Lab, Department of Biotechnology, Berhampur University, Bhanja Bihar, Berhampur, Odisha, 760007, India.
- Centre of Excellence on Bioprospecting of "Ethnopharmaceuticals of Southern Odisha" (CoE-BESO), Berhampur University, Bhanja Bihar, Berhampur, Odisha, 760007, India.
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EMMUNGİL H, İLGEN U, DİRESKENELİ RH. Autoimmunity in psoriatic arthritis: pathophysiological and clinical aspects. Turk J Med Sci 2021; 51:1601-1614. [PMID: 33581710 PMCID: PMC8569784 DOI: 10.3906/sag-2011-235] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 02/13/2021] [Indexed: 11/03/2022] Open
Abstract
Psoriatic arthritis (PsA) is an underdiagnosed entity with a broad impact on the quality of life. Although the pathogenesis is largely unknown, autoimmune footprints of the inflammation in PsA have increasingly been recognized. Most of the genetic variation predisposing to PsA is mapped to the class I major histocompatibility complex (MHC) region and shared by a variety of autoimmune diseases. Polymorphisms in the genes IL12B, IL23R, IL13, TNIP1, TRAF3IP2, TYK2, and many others explain the non- HLA genetic risk with little known functional consequences. Entheseal and synovial cellular infiltrate with oligoclonal CD8+ T cells and occasional germinal centers, loss of regulatory T cell function, and specific autoantibodies such as anti-PsA peptide, anti-LL-37, and anti-ADAMTSL5 are the immunopathological findings suggestive of autoimmunity. These were supported by clinical observations of autoimmune multimorbidity and treatment response to calcineurin/mTOR and co-stimulation inhibition.
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Affiliation(s)
- Hakan EMMUNGİL
- Division of Rheumatology, Department of Rheumatology, Trakya University Medical Faculty, EdirneTurkey
| | - Ufuk İLGEN
- Division of Rheumatology, Department of Rheumatology, Trakya University Medical Faculty, EdirneTurkey
| | - Rafi Haner DİRESKENELİ
- Division of Rheumatology, Department of Rheumatology, Marmara University Medical Faculty, İstanbulTurkey
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Du J, Wang X, Tan G, Liang Z, Zhang Z, Yu H. The association between genetic polymorphisms of interleukin 23 receptor gene and the risk of rheumatoid arthritis: An updated meta-analysis. Clin Immunol 2020; 210:108250. [DOI: 10.1016/j.clim.2019.108250] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 08/11/2019] [Accepted: 08/15/2019] [Indexed: 12/18/2022]
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Yang Y, Yuan S, Che M, Jing H, Yuan L, Dong K, Jin T. Genetic analysis of the relation between IL2RA/IL2RB and rheumatoid arthritis risk. Mol Genet Genomic Med 2019; 7:e00754. [PMID: 31134763 PMCID: PMC6625105 DOI: 10.1002/mgg3.754] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 04/10/2019] [Accepted: 04/27/2019] [Indexed: 01/10/2023] Open
Abstract
Background The biological mechanisms driving disease chronicity in rheumatoid arthritis (RA) are largely unidentified. Therefore, we aimed to determine genetic risk factors for RA. Methods In this case–control study, which includes samples from 499 patients and 507 healthy controls, six single‐nucleotide polymorphisms (SNPs) in interleukin‐2 receptor subunit alpha (IL2RA) and IL2RB were selected. Genotyping was performed using the Agena MassARRAY platform, and the statistical analyses were performed using the chi‐squared and Fisher's exact tests, genetic model analysis, and haplotype analysis. Result In the allele model, using the chi‐squared test, the result showed that rs791588 in IL2RA was associated with a decreased RA risk (odds ratios [OR] = 0.74, 95% confidence intervals [CI] = 0.62–0.89, p = 0.0014) after adjusting for age and gender. In the genetic model, logistic regression analyses revealed that rs791588 was associated with a decreased risk of RA under the codominant model, dominant model, recessive model, and log‐additive model. Stratification analysis revealed that two SNPs (rs791588 and rs2281089) were significantly associated with a reduced RA risk in an allele and genetic model after stratification by gender or age (p < 0.05). In addition, the haplotypes “Crs12569923Grs791588” and “Crs12569923Trs791588” of IL2RA was associated with an increased risk of RA adjusted by age and gender (OR = 1.35, 95% CI: 1.12–1.64, p = 0.0016; OR = 1.24, 95% CI: 1.03–1.48, p = 0.021). Conclusion This finding indicates that the inherited altered genetic constitution at IL2RA may predispose to a less destructive course of RA.
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Affiliation(s)
- Yonghui Yang
- Clinical Laboratory, Xi'an 630 Hospital, Yanliang, Xi'an, Shaanxi
| | - Shan Yuan
- Clinical Laboratory, Xi'an 630 Hospital, Yanliang, Xi'an, Shaanxi
| | - Meihua Che
- Clinical Laboratory, Xi'an 630 Hospital, Yanliang, Xi'an, Shaanxi
| | - Haiyin Jing
- Clinical Laboratory, Xi'an 630 Hospital, Yanliang, Xi'an, Shaanxi
| | - Limin Yuan
- Clinical Laboratory, Xi'an 630 Hospital, Yanliang, Xi'an, Shaanxi
| | - Kuaini Dong
- Clinical Laboratory, Xi'an 630 Hospital, Yanliang, Xi'an, Shaanxi
| | - Tianbo Jin
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China.,Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China.,Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China
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Mohammadi FS, Aslani S, Mostafaei S, Jamshidi A, Riahi P, Mahmoudi M. Are genetic variations in IL-21-IL-23R-IL-17A cytokine axis involved in a pathogenic pathway of rheumatoid arthritis? Bayesian hierarchical meta-analysis. J Cell Physiol 2019; 234:17159-17171. [PMID: 30924147 DOI: 10.1002/jcp.28495] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 02/16/2019] [Accepted: 02/20/2019] [Indexed: 12/24/2022]
Abstract
Inflammatory cytokines have been established to be involved in the pathogenesis of rheumatoid arthritis (RA). The genetic polymorphisms in the interleukin (IL) 23 receptor (IL23R), IL21, and IL17 have been associated with RA risk. However, there is no conclusive understanding of the genes encoding the immunoinflammatory IL-21-IL-23R-IL-17A pathway in RA aetiopathogenesis. This meta-analysis was conducted to attain this goal. A comprehensive literature search was conducted in Scopus and PubMed to look for the relevant case-control studies up until 2018. A Bayesian hierarchical meta-analysis was carried out to assess the association between the polymorphisms and the risk of RA. The association was estimated by calculating the logarithm of odds ratio (Log OR) and 95% credible interval (95% CI). In this meta-analysis, 37 case-control studies comprising 23,506 RA patients and 25,984 healthy individuals were found for analyzing the IL23R, IL21, and IL1A gene polymorphism and risk of RA. In the IL23R gene rs1343151 SNP, the minor A allele significantly increased the risk of RA (Log OR = 0.085, 95% CI = 0.008, 0.156). Moreover, the minor AA genotype was significantly associated with increased RA risk (Log OR = 0.176, 95% CI = 0.028, 0.321). In addition, the C allele of the IL23R gene rs2201841 SNP significantly decreased the disease risk (Log OR = -0.544, 95% CI = -1.0, -0.065). Since Bayesian meta-analysis is a powerful strategy to pool the data, it can be mentioned that genetic polymorphisms of IL23R, but not IL21 and IL17A, are involved in susceptibility to RA.
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Affiliation(s)
| | - Saeed Aslani
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Shayan Mostafaei
- Department of Community Medicine, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ahmadreza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Parisa Riahi
- Department of Biostatistics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Zou Q, Zhao Y, Wang Y, Fang Y, Liu Y. Associations between IL-23R gene polymorphisms and the susceptibility of rheumatoid arthritis: a meta-analysis. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:951-956. [PMID: 30942097 DOI: 10.1080/21691401.2019.1579731] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Qinghua Zou
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Rheumatology and Immunology, The First Hospital Affiliated to Army Medical University, Chongqing, China
| | - Yi Zhao
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, China
| | - Yong Wang
- Department of Rheumatology and Immunology, The First Hospital Affiliated to Army Medical University, Chongqing, China
| | - Yongfei Fang
- Department of Rheumatology and Immunology, The First Hospital Affiliated to Army Medical University, Chongqing, China
| | - Yi Liu
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, China
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Razawy W, van Driel M, Lubberts E. The role of IL-23 receptor signaling in inflammation-mediated erosive autoimmune arthritis and bone remodeling. Eur J Immunol 2018; 48:220-229. [PMID: 29148561 PMCID: PMC5838536 DOI: 10.1002/eji.201646787] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 11/10/2017] [Indexed: 12/15/2022]
Abstract
The IL‐23/Th17 axis has been implicated in the development of autoimmune diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). RA and PsA are heterogeneous diseases with substantial burden on patients. Increasing evidence suggests that the IL‐23 signaling pathway may be involved in the development of autoimmunity and erosive joint damage. IL‐23 can act either directly or indirectly on bone forming osteoblasts as well as on bone resorbing osteoclasts. As IL‐23 regulates the activity of cells of the bone, it is conceivable that in addition to inflammation‐mediated joint erosion, IL‐23 may play a role in physiological bone remodeling. In this review, we focus on the role of IL‐23 in autoimmune arthritis in patients and murine models, and provide an overview of IL‐23 producing and responding cells in autoimmune arthritic joints. In addition, we discuss the role of IL‐23 on bone forming osteoblasts and bone resorbing osteoclasts regarding inflammation‐mediated joint damage and bone remodeling. At last, we briefly discuss the clinical implications of targeting this pathway for joint damage and systemic bone loss in autoimmune arthritis.
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Affiliation(s)
- Wida Razawy
- Department of Rheumatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.,Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Marjolein van Driel
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Erik Lubberts
- Department of Rheumatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.,Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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Li J, Ye DQ. Response to the comment on ‘‘Relationship between the IL12B (rs3212227) gene polymorphism and susceptibility to multiple autoimmune diseases: A meta-analysis’’. Mod Rheumatol 2017; 27:180-181. [DOI: 10.1080/14397595.2016.1205779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Jun Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, PR China and
- Anhui Provincial Laboratory of Population Health and Major Disease Screening and Diagnosis, Anhui Medical University, Hefei, PR China
| | - Dong-Qing Ye
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, PR China and
- Anhui Provincial Laboratory of Population Health and Major Disease Screening and Diagnosis, Anhui Medical University, Hefei, PR China
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Wang MJ, Liu RP, Mi YY. Comment on "Relationship between the IL12B (rs3212227) gene polymorphism and susceptibility to multiple autoimmune diseases: a meta-analysis". Mod Rheumatol 2017; 27:178-179. [PMID: 27141973 DOI: 10.3109/14397595.2016.1170751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Ming-Jie Wang
- a Department of Orthopedics , Affiliated Hospital of Nanjing Medical University, Changzhou Second People's Hospital , Changzhou , China
| | - Rui-Ping Liu
- a Department of Orthopedics , Affiliated Hospital of Nanjing Medical University, Changzhou Second People's Hospital , Changzhou , China
| | - Yuan-Yuan Mi
- b Department of Urology , Third Affiliated Hospital of Nantong University , Wuxi , P.R. China
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Interleukin 12B gene polymorphisms and susceptibility to rheumatoid arthritis: a data synthesis. Clin Rheumatol 2016; 36:299-307. [PMID: 27312970 DOI: 10.1007/s10067-016-3327-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 05/02/2016] [Accepted: 06/08/2016] [Indexed: 10/21/2022]
Abstract
The aim of this study was to investigate the association of two common interleukin 12B (IL-12B) polymorphisms (rs3212227 and rs6887695) with rheumatoid arthritis (RA) susceptibility through meta-analyses. A systematic literature search of PubMed, Web of Science, Cochrane Library, and Embase databases was conducted on articles published before 28 February 2016. Then odds ratio (OR) with 95 % confidence interval (CI) was used to quantify the strength of association for homozygote, heterozygote, dominant, and recessive genetic models. Nine articles with a total of 17 case-control studies (12 for IL-12B rs3212227 polymorphism and 5 for IL-12B rs6887695 polymorphism) met our inclusion criteria. The pooled results demonstrated that IL-12B rs3212227 (homozygote model: OR = 0.96, 95 % CI = 0.81-1.15; heterozygote model: OR = 1.07, 95 % CI = 0.93-1.23; dominant model: OR = 1.05, 95 % CI = 0.91-1.20; recessive model: OR = 0.93, 95 % CI = 0.79-1.10) and rs6887695 (homozygote model: OR = 1.01, 95 % CI = 0.84-1.21; heterozygote model: OR = 1.14, 95 % CI = 0.86-1.51; dominant model: OR = 1.14, 95 % CI = 0.87-1.48; recessive model: OR = 1.01, 95 % CI = 0.85-1.21) polymorphisms may not be associated with RA risk. Our meta-analyses demonstrated that IL-12B rs3212227 and rs6887695 polymorphisms do not confer susceptibility to RA.
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Wang MJ, Xu XL, Mi YY, Liu RP. Association of IL12B Gene Polymorphisms with Rheumatoid Arthritis: A Meta-analysis. Arch Med Res 2016; 47:126-33. [PMID: 27155343 DOI: 10.1016/j.arcmed.2016.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 04/25/2016] [Indexed: 01/11/2023]
Abstract
BACKGROUND AND AIMS Currently published papers regarding the relationship between interleukin (IL)-12B gene polymorphisms and rheumatoid arthritis (RA) are contradictory. The aim of this meta-analysis was to evaluate the associations between the IL-12B gene polymorphisms (rs3122227 and rs6887695) and RA risk. METHODS We searched PubMed, Embase, the Cochrane Library and the China Knowledge Resource Integrated Database. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess associations between IL12B gene polymorphisms and RA. RESULTS A total of eight publications (4,409 cases and 5,591 controls) were included in this meta-analysis. The results demonstrated that rs3122227 and rs6887695 were not associated with RA risk based on current included studies. However, stratification analyses indicated rs6887695 was associated with RA in Asian patients. Rs3122227 was not related with RA in Asian or Caucasian patients. CONCLUSIONS Our data indicated that IL-12B gene polymorphisms were not related with RA. However, rs6887695 was associated with RA in Asian patients. Further larger-scale studies are urgently needed to identify the association between IL-12B gene polymorphisms and RA in Asian populations.
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Affiliation(s)
- Ming-Jie Wang
- Department of Orthopedics, Affiliated Hospital of Nanjing Medical University, Changzhou Second People's Hospital, Changzhou, China
| | - Xiao-Liang Xu
- Liver Surgery of Jiangsu Province People's Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuan-Yuan Mi
- Department of Urology, The Third Affiliated Hospital of Nantong University, Wuxi, PR China.
| | - Rui-Ping Liu
- Department of Orthopedics, Affiliated Hospital of Nanjing Medical University, Changzhou Second People's Hospital, Changzhou, China.
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Li J, Zhang C, Wang JB, Chen SS, Zhang TP, Li S, Pan HF, Ye DQ. Relationship between the IL12B (rs3212227) gene polymorphism and susceptibility to multiple autoimmune diseases: A meta-analysis. Mod Rheumatol 2016; 26:749-56. [PMID: 26915668 DOI: 10.3109/14397595.2016.1157282] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVES The purpose of this study was to evaluate whether a single-nucleotide polymorphism (SNP) IL12B 3(')UTR +1188A/C (rs3212227) confers susceptibility to several autoimmune diseases. METHODS A systematic literature search was conducted to identify relevant studies. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to estimate the strength of association. RESULTS Twenty-five studies were included in the meta-analysis, which contained 9794 cases and 11,330 controls. Our result indicated that IL12B +1188A/C (rs3212227) polymorphism was associated with type-1 diabetes (T1D) in the dominant model (p = 0.008), and an increased risk was found in East Asians in the dominant model (p < 0.001). East Asians rheumatoid arthritis (RA) patients seemed to be at risk of allelic model (p = 0.011). As to Behcet's disease (BD), there was a risk in dominant model (p = 0.020) and positive associations of dominant model, allelic model in East Asians (p = 0.009; p < 0.001, respectively). But we failed to find any association between IL12B +1188A/C (rs3212227) polymorphism with Graves' disease (GD) and ankylosing spondylitis (AS). CONCLUSIONS The present study suggests that the IL12B +1188A/C (rs3212227) polymorphism might be associated with genetic susceptibility to autoimmune diseases, such as T1D, RA, BD, but not GD and AS.
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Affiliation(s)
- Jun Li
- a Department of Epidemiology and Biostatistics, School of Public Health , Anhui Medical University , Hefei , P.R. China and.,b Anhui Provincial Laboratory of Population Health & Major Disease Screening and Diagnosis , Anhui Medical University , Hefei , P.R. China
| | - Chao Zhang
- a Department of Epidemiology and Biostatistics, School of Public Health , Anhui Medical University , Hefei , P.R. China and.,b Anhui Provincial Laboratory of Population Health & Major Disease Screening and Diagnosis , Anhui Medical University , Hefei , P.R. China
| | - Jie-Bing Wang
- a Department of Epidemiology and Biostatistics, School of Public Health , Anhui Medical University , Hefei , P.R. China and.,b Anhui Provincial Laboratory of Population Health & Major Disease Screening and Diagnosis , Anhui Medical University , Hefei , P.R. China
| | - Shuang-Shuang Chen
- a Department of Epidemiology and Biostatistics, School of Public Health , Anhui Medical University , Hefei , P.R. China and.,b Anhui Provincial Laboratory of Population Health & Major Disease Screening and Diagnosis , Anhui Medical University , Hefei , P.R. China
| | - Tian-Ping Zhang
- a Department of Epidemiology and Biostatistics, School of Public Health , Anhui Medical University , Hefei , P.R. China and.,b Anhui Provincial Laboratory of Population Health & Major Disease Screening and Diagnosis , Anhui Medical University , Hefei , P.R. China
| | - Si Li
- a Department of Epidemiology and Biostatistics, School of Public Health , Anhui Medical University , Hefei , P.R. China and.,b Anhui Provincial Laboratory of Population Health & Major Disease Screening and Diagnosis , Anhui Medical University , Hefei , P.R. China
| | - Hai-Feng Pan
- a Department of Epidemiology and Biostatistics, School of Public Health , Anhui Medical University , Hefei , P.R. China and.,b Anhui Provincial Laboratory of Population Health & Major Disease Screening and Diagnosis , Anhui Medical University , Hefei , P.R. China
| | - Dong-Qing Ye
- a Department of Epidemiology and Biostatistics, School of Public Health , Anhui Medical University , Hefei , P.R. China and.,b Anhui Provincial Laboratory of Population Health & Major Disease Screening and Diagnosis , Anhui Medical University , Hefei , P.R. China
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Association between polymorphisms of interleukin 12 and rheumatoid arthritis associated biomarkers in a Chinese population. Cytokine 2015; 76:363-367. [PMID: 26375522 DOI: 10.1016/j.cyto.2015.09.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2015] [Revised: 08/17/2015] [Accepted: 09/08/2015] [Indexed: 12/19/2022]
Abstract
INTRODUCTION The aim of the present study was to examine the association between polymorphisms of interleukin 12 (IL-12) and rheumatoid arthritis (RA) associated biomarkers in a Chinese population. MATERIALS AND METHODS We studied IL-12A rs2243115 T/G and IL-12B rs3212227 A/C polymorphisms in 615 RA patients and 839 controls in a Chinese population. Genotyping was done by a custom-by-design 48-Plex SNPscan™ Kit. The plasma level of IL-12 was measured by an enzyme-linked immune-sorbent assay in 90 RA patients and 90 controls. Clinical data with other potential diagnostic value were provided by the physicians. RESULTS A significantly increased risk for RA associated with the IL-12A rs2243115 GG (GG versus TT: OR=4.81, 95% CI 1.33-17.36, P=0.017; and GG versus TG+TT: OR=4.55, 95% CI 1.27-16.36, P=0.020) genotype was evident among rheumatoid factor (RF) negative patients, and with the IL-12B rs3212227 AC (AC versus AA) and AC+CC (AC+CC versus AA) genotypes were evident among older patients (OR=1.48, 95% CI 1.06-2.06, P=0.020), RF positive patients (OR=1.35, 95% CI 1.04-1.75, P=0.026) and anti-cyclic citrullinated peptide antibodies (ACPA) negative patients (OR=1.53, 95% CI 1.11-2.10, P=0.009). The plasma level of IL-12 was significantly higher in RA patients (P<0.001). IL-12 plasma level of IL-12A rs2243115 TT (P<0.001) and IL-12B rs3212227 C allele (P<0.001) were significantly higher in RA patients than controls respectively. The plasma level of IL-12 of RF positive RA patients was significantly higher than RF negative patients (P=0.008), especially in rs3212227 AC patients (P=0.01). CONCLUSIONS These findings suggested that the functional single nucleotide polymorphism (SNP) IL-12A rs2243115 GG genotype may increase the risk of RA in RF negative patients, and the IL-12B rs3212227 AC and AC+CC genotypes are associated with RA risk in older patients, RF positive patients and ACPA negative patients. The IL-12A rs2243115 T/G and IL-12B rs3212227 A/C allele might also impact the inflammatory reaction of IL-12 in patients with RA.
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Hamdy G, Darweesh H, Fawzy S, Khattab EA, Fawzy E, Sheta M. Association of interleukin-23 receptor (IL-23R) gene polymorphisms (rs11209026, rs2201841 and rs10889677) with Egyptian rheumatoid arthritis patients. THE EGYPTIAN RHEUMATOLOGIST 2015. [DOI: 10.1016/j.ejr.2014.12.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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16
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Hamdy G, Darweesh H, Khattab EA, Fawzy S, Fawzy E, Sheta M. Evidence of association of interleukin-23 receptor gene polymorphisms with Egyptian rheumatoid arthritis patients. Hum Immunol 2015; 76:417-20. [DOI: 10.1016/j.humimm.2015.03.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Revised: 05/22/2014] [Accepted: 03/31/2015] [Indexed: 11/30/2022]
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Emami S, Ziaee V, Rezaei A, Sadr M, Maddah M, Amirzargar AA, Rezaei N. IL23Rgene polymorphism with juvenile idiopathic arthritis and its association with serum IL-17A. Int J Rheum Dis 2015; 19:1189-1196. [DOI: 10.1111/1756-185x.12674] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Samira Emami
- Department of Immunology; School of Medicine; Tehran Iran
| | - Vahid Ziaee
- Pediatric Rheumatology Research Group; Rheumatology Research Center; Tehran Iran
- Pediatrics Center of Excellence; Tehran Iran
| | - Arezou Rezaei
- Research Center for Immunodeficiencies; Children's Medical Center; Tehran Iran
| | - Maryam Sadr
- Molecular Immunology Research Center; Tehran University of Medical Sciences; Tehran Iran
| | | | - Ali Akbar Amirzargar
- Department of Immunology; School of Medicine; Tehran Iran
- Molecular Immunology Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Nima Rezaei
- Department of Immunology; School of Medicine; Tehran Iran
- Research Center for Immunodeficiencies; Children's Medical Center; Tehran Iran
- Molecular Immunology Research Center; Tehran University of Medical Sciences; Tehran Iran
- Universal Scientific Education and Research Network (USERN); Tehran Iran
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18
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Wang EY, Yang Q, Liao ZG. Association of polymorphisms in interleukin (IL)-12A and -B genes with rheumatoid arthritis in a Chinese population. Clin Exp Immunol 2015; 180:83-9. [PMID: 25469793 DOI: 10.1111/cei.12563] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/28/2014] [Indexed: 02/03/2023] Open
Abstract
Rheumatoid arthritis (RA) is characterized by synovial infiltrates and progressive cell-mediated destruction of the joints, which results in significant disability and early mortality. Genetic factors may play an important role in the development of RA. The aim of this study was to investigate the association of common polymorphisms in interleukin (IL)-12A and IL-12B genes with RA in a Chinese Han population. Three single nucleotide polymorphisms (SNPs) in IL-12 genes were genotyped in 412 patients with RA and 279 control subjects using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Our data showed that IL-12B gene SNPs rs3212227 and rs6887695 were observed as a risk factor of RA. The minor allele (C) frequency of IL-12B gene rs3212227 and rs6887695 increased the risk of RA. Individuals carrying the rs3212227/rs6887695 C/C haplotype were associated with a significantly increased risk of RA. RA patients with the C allele of IL-12B gene rs6887695 was a protective factor to erosive arthropathy. Carriers of the C allele of IL-12B gene rs3212227 were significantly more likely to be RF-positive. No significant association was observed between rs2243115 in IL-12A and RA, due probably to the limited power. These results suggest that common variants in IL-12B may contribute to the development of RA in the Chinese population.
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Affiliation(s)
- E-Y Wang
- Department of Reproductive Medical Center, The First Hospital of Zhengzhou University, Zhengzhou, China
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Magyari L, Varszegi D, Kovesdi E, Sarlos P, Farago B, Javorhazy A, Sumegi K, Banfai Z, Melegh B. Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications. World J Orthop 2014; 5:516-536. [PMID: 25232528 PMCID: PMC4133458 DOI: 10.5312/wjo.v5.i4.516] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 04/05/2014] [Accepted: 05/16/2014] [Indexed: 02/06/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease, resulting in a chronic, systemic inflammatory disorder. It may affect many tissues and organs, but it primarily affects the flexible joints. In clinical practice patient care generates many questions about diagnosis, prognosis, and treatment. It is challenging for health care specialists to keep up to date with the medical literature. This review summarizes the pathogenesis, the polymorphisms of interleukin and interleukin genes and the standard available and possible future immunologic targets for RA treatment. The identification of disease-associated interleukin and interleukin receptor genes can provide precious insight into the genetic variations prior to disease onset in order to identify the pathways important for RA pathogenesis. The knowledge of the complex genetic background may prove useful for developing novel therapies and making personalized medicine based on the individual’s genetics.
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20
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Song GG, Bae SC, Choi SJ, Ji JD, Lee YH. Associations between interleukin-23 receptor polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. Mol Biol Rep 2012; 39:10655-63. [PMID: 23053963 DOI: 10.1007/s11033-012-1955-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Accepted: 10/01/2012] [Indexed: 12/15/2022]
Abstract
The aim of this study was to determine whether interleukin-23 receptor (IL-23R) polymorphisms confer susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between the IL-23R rs1343151, rs10489629, rs7517847, rs11209026, rs1004819, and rs2201841 polymorphisms and RA using (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 13 studies from eight articles involving 10,016 RA patients and 11,967 controls were considered in the meta-analysis. Meta-analysis identified a significant association between RA and the A allele of the rs1343151 polymorphism in the overall population (OR = 1.110, 95 % CI = 1.056-1.168, p = 4.7 × 10(-6)). Stratification by ethnicity identified a significant association between this polymorphism and RA in Europeans (OR = 1.105, 95 % CI = 1.049-1.163, p = 1.4 × 10(-5)). An association was also found between RA and the A allele carrier of the rs1343151 polymorphism in Europeans (OR = 1.135, 95 % CI = 1.058-1.217, p = 4.0 × 10(-5)). Meta-analysis revealed a significant association between RA and the A allele of the rs10489629 polymorphism in the overall population (OR = 1.079, 95 % CI = 1.029-1.131, p = 0.002) and in Europeans (OR = 1.092, 95 % CI = 1.038-1.149, p = 0.001). Meta-analyses of recessive, dominant, and additive models showed the same pattern as the meta-analysis of the A allele of the rs10489629 polymorphism, that is, a significant association with RA in Europeans. However, no association was found between the IL-23R rs7517847, rs11209026, rs1004819, and rs2201841 polymorphisms and RA susceptibility. This meta-analysis shows that the IL-23R rs1343151 and rs10489629 polymorphisms are associated with the development of RA in Europeans. These findings suggest that the IL-23R genes confer susceptibility to RA in the European population, but further study of this association is required in other ethnic groups.
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Affiliation(s)
- Gwan Gyu Song
- Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5 ga Seongbuk-gu, Seoul, 136-705, Korea
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IL-23A, IL-23R, IL-17A and IL-17R polymorphisms in different psoriatic arthritis clinical manifestations in the northern Italian population. Rheumatol Int 2012; 33:1165-76. [PMID: 22955875 DOI: 10.1007/s00296-012-2501-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2012] [Accepted: 08/23/2012] [Indexed: 01/05/2023]
Abstract
To investigate the genetic variability of IL-17A, IL17-RA, IL-23A and IL-23R genes on an in-depth phenotypically characterized northern Italian Psoriatic arthritis (PsA) case-control cohort, in search for associations specific to different PsA clinical sub-phenotypes. We examined 118 patients with PsA according to CASPAR criteria (mean age 57 ± 13, female 38.4 %, mean disease duration 13.9 ± 8.6 years, peripheral disease 83.8 %, axial manifestations 34.5 %, radiological erosive disease 49 %) compared with 248 controls of the same ethnic origin matched for age and sex. The presence of axial disease was defined by the clinical axial involvement and/or the presence of radiological alteration consistent with spondyloarthropathy according to New York criteria. The presence of peripheral disease (arthritis and/or enthesitis) was defined only on clinical basis. A total of 40 SNPs, mapping within the genes mentioned above, were genotyped in both groups and used to perform association analyses by subdividing the PsA sample into subgroups according to different clinical manifestations on the basis of axial and peripheral involvements. No differences between patients and controls were found in the distribution of the IL-17A, IL17-RA, IL-23A and IL-23R genes allelic variants. Comparing patients with axial disease versus those without, we found that axial manifestations were significantly associated with the presence of IL-23R rs12401432 GG homozygosity (26.8 % vs. 5.3 %, p corr = 0.019, OR 2.63 [95 % CI 1.13-6.16]). No differences in distribution of the allelic variants were found comparing patients with versus those without peripheral disease or patients with versus without radiological peripheral erosions. In PA patients of northern Italian origin, IL-17A, IL17-RA, IL-23A and IL-23R genes allelic variants are not associated with disease susceptibility. However, a strong association with the IL-23RA rs12401432 GG genotype is associated with axial involvement of the disease.
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van Wanrooij RLJ, Zwiers A, Kraal G, Bouma G. Genetic variations in interleukin-12 related genes in immune-mediated diseases. J Autoimmun 2012; 39:359-68. [PMID: 22819329 DOI: 10.1016/j.jaut.2012.06.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Revised: 06/13/2012] [Accepted: 06/24/2012] [Indexed: 12/20/2022]
Abstract
The interleukin-12 (IL-12) family comprises a group of heterodimeric cytokines and their respective receptors that play key roles in immune responses. A growing number of autoimmune diseases has been found to be associated with genetic variation in these genes. Based on their respective associations with the IL-12 genes, autoimmune diseases appear to cluster in two groups that either show strong associations with the Th1/Th17 pathway (as indicated by genetic association with IL12B and IL23R) or the Th1/IL-35 pathway as the consequence of their association with polymorphisms in the IL12A gene region. The genetic associations are described in relation to what is known of the functionality of these genes in the various diseases. Comparing association data for gene families in different diseases may lead to better insight in the function of the genes in the onset and course of the disease.
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Affiliation(s)
- R L J van Wanrooij
- Department of Gastroenterology and Hepatology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
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Glas J, Seiderer J, Wagner J, Olszak T, Fries C, Tillack C, Friedrich M, Beigel F, Stallhofer J, Steib C, Wetzke M, Göke B, Ochsenkühn T, Diegelmann J, Czamara D, Brand S. Analysis of IL12B gene variants in inflammatory bowel disease. PLoS One 2012; 7:e34349. [PMID: 22479607 PMCID: PMC3316707 DOI: 10.1371/journal.pone.0034349] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2011] [Accepted: 02/26/2012] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD). However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS We analyzed IL12B gene variants regarding association with Crohn's disease (CD) and ulcerative colitis (UC). Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region (rs3212227, rs17860508, rs10045431, rs6887695). Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD (p = 0.035; OR 1.15 [95% CI 1.01-1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99-1.31], p = 0.066) and UC (OR 1.18 [0.97-1.43], p = 0.092). CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p = 6.8×10(-5); OR = 2.84, 95% CI 1.66-4.84), while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p = 0.029; OR = 0.36, 95% CI 0.14-0.92). In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor RORα which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694) in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 (p<0.05) but there was no epistasis between IL23R and IL12B variants. CONCLUSIONS/SIGNIFICANCE The IL12B SNP rs6887695 modulates the susceptibility and the phenotype of IBD, although the effect on IBD susceptibilty is less pronounced than that of IL23R gene variants.
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Affiliation(s)
- Jürgen Glas
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
- Department of Preventive Dentistry and Periodontology, LMU, Munich, Germany
- Department of Human Genetics, Rheinisch-Westfälische Technische Hochschule (RWTH), Aachen, Germany
| | - Julia Seiderer
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Johanna Wagner
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
- Department of Preventive Dentistry and Periodontology, LMU, Munich, Germany
| | - Torsten Olszak
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
- Division of Gastroenterology, Brigham & Women's Hospital, Harvard Medical School, Boston, United States of America
| | - Christoph Fries
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
- Department of Preventive Dentistry and Periodontology, LMU, Munich, Germany
| | - Cornelia Tillack
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Matthias Friedrich
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
- Department of Preventive Dentistry and Periodontology, LMU, Munich, Germany
| | - Florian Beigel
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Johannes Stallhofer
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Christian Steib
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Martin Wetzke
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
- Department of Preventive Dentistry and Periodontology, LMU, Munich, Germany
- Department of Pediatrics, Hannover Medical School, Hannover, Germany
| | - Burkhard Göke
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Thomas Ochsenkühn
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Julia Diegelmann
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
- Department of Preventive Dentistry and Periodontology, LMU, Munich, Germany
- * E-mail: (JD); (SB)
| | | | - Stephan Brand
- Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany
- * E-mail: (JD); (SB)
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Chen-Xu M, Topless R, McKinney C, Merriman ME, Phipps-Green A, Dalbeth N, Gow PJ, Harrison AA, Highton J, Jones PB, Nissen M, Smith MD, van Rij A, Jones GT, Rodriguez-Rodriguez L, Fernandez-Gutierrez B, Teruel M, Balsa A, Pascual-Salcedo D, Ortiz AM, Gonzalez-Gay MA, Steer S, Maehlen M, Lie B, Wordsworth BP, Stamp LK, Martin J, Merriman TR. Replication of association of the interleukin 23 receptor rs1343151 variant with rheumatoid arthritis in Caucasian sample sets. Ann Rheum Dis 2012; 71:155-7. [PMID: 21926184 DOI: 10.1136/annrheumdis-2011-200591] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Hueber AJ, Asquith DL, McInnes IB, Miller AM. Embracing novel cytokines in RA – complexity grows as does opportunity! Best Pract Res Clin Rheumatol 2010; 24:479-87. [DOI: 10.1016/j.berh.2010.01.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Abstract
Until recently, autoimmune diseases had been categorized as either Th1- or Th2-mediated diseases. However, the discovery of a novel subset of helper T cells producing interleukin (IL)-17, ie, Th17 cells, changed this paradigm. Currently, IL-17 and Th17 cells are implicated in many autoimmune diseases, such as rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel diseases. Such conclusions were initially drawn from observations in animal models of autoimmune diseases, and accumulating data from clinical research also support the involvement of IL-17 in human diseases as well. Reagents targeting Th17-related molecules have been under clinical investigation for some diseases but have not always been effective in controlling disease activity. Consistent with this, it has become evident that there are substantial differences in the development of Th17 cells and in the way they function in autoimmune diseases between humans and experimental animals. Thus, further investigation is needed before we can draw any conclusions about the importance of IL-17 and Th17 cells in human autoimmune diseases.
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Affiliation(s)
- Hisakata Yamada
- Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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27
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Affiliation(s)
- Hisakata YAMADA
- Division of Host Defense, Medical Institute of Bioregulation, Kyushu University
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Khan S, Greenberg JD, Bhardwaj N. Dendritic cells as targets for therapy in rheumatoid arthritis. Nat Rev Rheumatol 2009; 5:566-71. [PMID: 19798032 DOI: 10.1038/nrrheum.2009.185] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Dendritic cells (DCs) are central in inducing immunity and in mediating immune tolerance in their role as professional antigen-presenting cells. In the absence of DCs, a fatal autoimmunity develops in animal models. Although the role of DCs has been investigated extensively in the pathogenesis of rheumatoid arthritis (RA), it remains unclear whether DCs initiate autoimmunity in this disease. Nevertheless, evidence points towards a significant role for DCs in disease maintenance and progression. Current biologic therapies target cytokine products of antigen-presenting cells, such as tumor necrosis factor, interleukin-1 and interleukin-6. Emerging therapies for RA exploit the tolerogenic capacity of DCs. 'Tolerogenic' DCs can be generated from myeloid precursors ex vivo, loaded with antigen, and manipulated to suppress autoimmune responses in vivo, through the induction of activation-induced cell death, anergy, and/or regulatory T cells. Cells that are primed by DCs, such as B cells, type 1 and type 17 T helper cells, and that have been implicated in certain models of autoimmunity, are also being considered as additional targets for immune-based therapy. Studies to validate these approaches to ameliorate autoimmunity will be necessary before their application in the clinic.
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Affiliation(s)
- Shaukat Khan
- Cancer Institute, New York University Langone Medical Center, and New York University Hospital for Joint Diseases, New York, NY 10016, USA
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Hillyer P, Larché MJ, Bowman EP, McClanahan TK, de Waal Malefyt R, Schewitz LP, Giddins G, Feldmann M, Kastelein RA, Brennan FM. Investigating the role of the interleukin-23/-17A axis in rheumatoid arthritis. Rheumatology (Oxford) 2009; 48:1581-9. [PMID: 19815670 PMCID: PMC2777488 DOI: 10.1093/rheumatology/kep293] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Objective. IL-23 is a pro-inflammatory cytokine proposed to be central to the development of autoimmune disease. We investigated whether IL-23, together with the downstream mediator IL-17A, was present and functional in RA in humans. Methods. RA synovial cells were cultured in the presence or absence of antibodies directed against IL-23p19 or -23R and -17. IL-23, -12, -17, and their receptors, and IL-6, -1β and TNF-α were measured by ELISA and/or PCR. Results. Small amounts of cell-associated IL-23 (median 110 pg/ml) were detected in RA synovial cultures, and found to be functional as IL-23R blockade resulting in a significant inhibition of TNF-α (57%), IL-1β (51%) and IL-6 (30%). However, there was a considerable variability between individual patient samples, and anti-IL-23p19 was found to be considerably less effective. IL-17A protein was detected in ∼40% of the supernatants and IL-17A blockade, in IL-17A-producing cultures, resulted in a small but significant inhibition of TNF-α (38%), IL-1β (23%) and IL-6 (22%). Addition of recombinant IL-23 to cultures had a variable effect on the spontaneous production of endogenous IL-17A with enhancement observed in some but not all cultures, suggesting that either the low levels of endogenous IL-23 are sufficient to support cytokine production and/or that the relevant Th17 cells were not present. Conclusions. These results suggest that although IL-23 may have pathogenic activity in a proportion of patients with late-stage RA, it is not abundantly produced in this inflammatory tissue, nor does it have a dominant role in all patient tissues analysed.
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Affiliation(s)
- Philippa Hillyer
- Kennedy Institute of Rheumatology, Imperial College London, 1 Aspenlea Road, London W6 8LH, UK
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Hollis-Moffatt JE, Merriman ME, Rodger RA, Rowley KA, Chapman PT, Dalbeth N, Gow PJ, Harrison AA, Highton J, Jones PBB, O'Donnell JL, Stamp LK, Merriman TR. Evidence for association of an interleukin 23 receptor variant independent of the R381Q variant with rheumatoid arthritis. Ann Rheum Dis 2009; 68:1340-4. [PMID: 18647855 DOI: 10.1136/ard.2008.090142] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE The rare allele of a non-synonymous interleukin 23 receptor (IL23R) single nucleotide polymorphism (SNP) rs11209026 (p.Arg381Gln) confers strong protection against Crohn disease (CD) and psoriasis. Other IL23R variants also exhibit association with CD, genetically independent of rs11209026. In rheumatoid arthritis (RA), IL23 is an important determinant of the production of IL17A, a cytokine of consequence in inflammation and bone destruction. While there is no previous support for strong association of IL23R with RA, the possibility of a weaker role for IL23R variants in the aetiology of RA cannot be eliminated. METHODS A New Zealand RA cohort was tested for association with six IL23R SNPs and the resulting data combined with a reanalysis of the Wellcome Trust Case Control Consortium data and a previously published Spanish data set. The combined data set totals over 3000 Caucasian cases and 3800 controls, which has sufficient power to detect a risk of as low as odds ratio (OR) = 1.2. RESULTS Our data emphasise the lack of association of rs11209026 with RA (OR 1.01, 95% confidence interval (CI) 0.88 to 1.16, p = 0.86). However there was some evidence for association of rs1343151 with RA (OR 1.14, 95% CI 1.06 to 1.22, p = <0.001). CONCLUSIONS While requiring further replication, these data further support a role for the IL17A/IL23 pathway in RA. Understanding how different variants of IL23R associate, at varying levels of strength, with contrasting groups of immune-mediated diseases (CD, psoriasis, ankylosing spondylitis, RA) will enhance knowledge on the aetiology of these diseases.
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31
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Smith RL, Warren RB, Griffiths CEM, Worthington J. Genetic susceptibility to psoriasis: an emerging picture. Genome Med 2009; 1:72. [PMID: 19638187 PMCID: PMC2717398 DOI: 10.1186/gm72] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Psoriasis is recognized as a complex disease for which multiple genetic and non-genetic factors influence susceptibility. The major susceptibility locus resides in the MHC class I region and, until relatively recently, evidence for non-MHC loci was inconsistent. Like many common diseases, knowledge of the genetic basis of this condition has been advanced dramatically in recent times with the advent of genome-wide association studies using single nucleotide polymorphisms. Here, we give an overview of current knowledge of genetic risk factors for psoriasis and consider emerging studies that may further add to our understanding of the genetic basis of the disease.
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Affiliation(s)
- Rhodri Ll Smith
- ARC Epidemiology Unit, University of Manchester, Manchester, M13 9PT, UK
| | - Richard B Warren
- Dermatological Sciences, Salford Royal Hospital, Manchester Academic Health Science Centre, UK
| | | | - Jane Worthington
- ARC Epidemiology Unit, University of Manchester, Manchester, M13 9PT, UK
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32
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Varade J, Ramón Lamas J, Rodríguez L, Fernández-Arquero M, Loza-Santamaría E, Jover JA, de la Concha EG, Fernández-Gutierrez B, Urcelay E, Martínez A. IL23R and IL12B genes: susceptibility analysis in rheumatoid arthritis. Ann Rheum Dis 2009; 68:1230-2. [PMID: 19525409 DOI: 10.1136/ard.2008.099275] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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McGonagle D, Aziz A, Dickie LJ, McDermott MF. An integrated classification of pediatric inflammatory diseases, based on the concepts of autoinflammation and the immunological disease continuum. Pediatr Res 2009; 65:38R-45R. [PMID: 19190531 DOI: 10.1203/pdr.0b013e31819dbd0a] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Historically, pediatric inflammatory diseases were viewed as autoimmune but developments in genetics of monogenic disease have supported our proposal that "inflammation against self" be viewed as an immunologic disease continuum (IDC), with genetic disorders of adaptive and innate immunity at either end. Innate immune-mediated diseases may be associated with significant tissue destruction without evident adaptive immune responses and are designated as autoinflammatory due to distinct immunopathologic features. However, the majority of pediatric inflammatory disorders are situated along this IDC. Innate immunity has been demonstrated in polygenic disorders, particularly Crohn's disease (CD). A genetic overlap exists between CD and some major histocompatibility complex (MHC) class I-associated diseases, including psoriasis; these diseases seem to represent a true intermediate between autoinflammation and autoimmunity. Conversely, classical autoimmune diseases, with autoantibody and MHC class II associations, including celiac disease and rheumatoid arthritis (RA), have adaptive immune genetic associations, including Cytotoxic T-Lymphocyte Antigen-4 (CTLA4) and PTPN22. This proposed classification is clinically relevant, because innate immune-mediated disorders may respond to cytokine antagonism whereas autoimmune-mediated diseases respond better to anti-T and B cell therapies. Furthermore, the etiopathogenesis of poorly defined "autoimmune" diseases, such as juvenile idiopathic arthritis, may be inferred to have substantial innate immune involvement, based on response to IL-1 antagonism.
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Affiliation(s)
- Dennis McGonagle
- NIHR-Leeds Molecular Biology Research Unit (NIHR-LMBRU), University of Leeds, Leeds LS9 7TF, United Kingdom
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Einarsdottir E, Koskinen LLE, Dukes E, Kainu K, Suomela S, Lappalainen M, Ziberna F, Korponay-Szabo IR, Kurppa K, Kaukinen K, Adány R, Pocsai Z, Széles G, Färkkilä M, Turunen U, Halme L, Paavola-Sakki P, Not T, Vatta S, Ventura A, Löfberg R, Torkvist L, Bresso F, Halfvarson J, Mäki M, Kontula K, Saarialho-Kere U, Kere J, D'Amato M, Saavalainen P. IL23R in the Swedish, Finnish, Hungarian and Italian populations: association with IBD and psoriasis, and linkage to celiac disease. BMC MEDICAL GENETICS 2009; 10:8. [PMID: 19175939 PMCID: PMC2642807 DOI: 10.1186/1471-2350-10-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Accepted: 01/28/2009] [Indexed: 12/24/2022]
Abstract
Background Association of the interleukin-23 receptor (IL23R) with inflammatory bowel disease (IBD) has been confirmed in several populations. IL23R also associates with psoriasis, suggesting that the gene may be an important candidate for many chronic inflammatory diseases. Methods We studied association of single-nucleotide variants in IL23R with IBD in Swedish patients, in both Crohn's disease (CD) and ulcerative colitis (UC) subsets. The same genetic variants were also studied in Finnish patients with psoriasis or celiac disease, and in Hungarian and Italian patients with celiac disease. Results Association of IL23R with IBD was replicated in our Swedish patients, and linkage and association of the IL23R region with psoriasis was found in the Finnish population. The IL23R region was also linked to celiac disease in Finnish families, but no association of IL23R variants with celiac disease was found in the Finnish, Hungarian or Italian samples. Conclusion Our study is the first to demonstrate association of IL23R with CD and UC in Swedish patients with IBD. It is also the first study to report linkage and association of the IL23R region with psoriasis in the Finnish population. Importantly, this is the first report of linkage of the IL23R region to celiac disease, a chronic inflammatory condition in which IL23R has not been previously implicated.
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Affiliation(s)
- Elisabet Einarsdottir
- Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
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Lyakh L, Trinchieri G, Provezza L, Carra G, Gerosa F. Regulation of interleukin-12/interleukin-23 production and the T-helper 17 response in humans. Immunol Rev 2008; 226:112-31. [PMID: 19161420 PMCID: PMC2766610 DOI: 10.1111/j.1600-065x.2008.00700.x] [Citation(s) in RCA: 166] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Interleukin-12 (IL-12) and IL-23 share a common chain. Yet, their production in response to pathogens is differentially regulated, and their functions are distinct and often antithetic. IL-12 is involved in the induction or amplification of the T-helper (Th) type 1 response, whereas IL-23 has been associated with the generation of the Th17 response and IL-17 production. Mycobacterium tuberculosis and yeast zymosan induce IL-23, but in the absence of other stimuli, no IL-12 is induced in human dendritic cells (DCs). The stimulation of IL-23 by M. tuberculosis was mostly explained by the triggering of Toll-like receptor (TLR2) and the cytoplasmic receptor nucleotide oligomerization domain (NOD)-containing protein 2, whereas zymosan induces IL-23 primarily by stimulating the beta-glucan receptor dectin-1 alone or in combination with TLR2. IL-23, IL-6, transforming growth factor (TGF-beta1), and IL-1beta in supernatants from activated human DCs induce human naive CD4(+) T cells to produce IL-17. These data are consistent with various recent reports that TGF-beta is an inducer of IL-17 production both in human and in mouse cells. However, IL-1 is necessary in combination with some or all of the other cytokines to induce IL-17 production in human T cells. The ability of various stimuli to induce Th17 cells depends not only on their induction of IL-23, IL-6, and TGF-beta production in DCs but also on their ability to activate directly or indirectly the inflammasome and to induce IL-1beta.
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Affiliation(s)
- Lyudmila Lyakh
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Giorgio Trinchieri
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Lisa Provezza
- Department of Pathology, Section of Immunology, University of Verona, Italy
| | - Giuseppe Carra
- Department of Pathology, Section of Immunology, University of Verona, Italy
| | - Franca Gerosa
- Department of Pathology, Section of Immunology, University of Verona, Italy
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Prahalad S, Glass DN. A comprehensive review of the genetics of juvenile idiopathic arthritis. Pediatr Rheumatol Online J 2008; 6:11. [PMID: 18644131 PMCID: PMC2515830 DOI: 10.1186/1546-0096-6-11] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2008] [Accepted: 07/21/2008] [Indexed: 12/29/2022] Open
Abstract
Juvenile idiopathic arthritis (JIA) is the most common chronic arthropathy of childhood which is believed to be influenced by both genetic and environmental factors. The progress in identifying genes underlying JIA susceptibility using candidate gene association studies has been slow. Several associations between JIA and variants in the genes encoding the human leukocyte antigens (HLA) have been confirmed and replicated in independent cohorts. However it is clear that genetic variants outside the HLA also influence susceptibility to JIA. While a large number of non-HLA candidate genes have been tested for associations, only a handful of reported associations such as PTPN22 have been validated. In this review we discuss the principles behind genetic studies of complex traits like JIA, and comprehensively catalogue non-HLA candidate-gene association studies performed in JIA to date and review several validated associations. Most candidate gene studies are underpowered and do not detect associations, and those that do are often not replicated. We also discuss the principles behind genome-wide association studies and discuss possible implications for identifying genes underlying JIA. Finally we discuss several genetic variants underlying multiple clinically distinct autoimmune phenotypes.
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Affiliation(s)
- Sampath Prahalad
- Assistant Professor of Pediatrics, Division of Immunology and Rheumatology, Department of Pediatrics, University of Utah School of Medicine, P.O Box 581289 Salt Lake City, UT 84158-1289, USA
| | - David N Glass
- Professor of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 7030, Cincinnati, OH 45229, USA
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