Association study in Romanians confirms IL23A gene haplotype block rs2066808/rs11171806 as conferring risk to psoriatic arthritis
Introduction
Psoriatic arthritis (PsA) is a chronic immune-mediated disease in which psoriatic skin lesions are accompanied by peripheral and/or axial joints inflammation [1]. The cytokines IL12 and IL23 have been recently implicated in the pathogenesis of this condition [2], [3], [4]. Different studies have shown that IL23 expression is increased in the psoriatic skin lesions, thus contributing to the maintenance of chronic inflammatory process [5]. These findings have been already translated into practice, since biological treatment against the common subunit of IL12/23 (IL12p40) has become a recognized option in management of psoriasis and PsA [6].
IL12 and IL23 are similar in structure, both being heterodimeric proteins with IL12p35 and IL23p19 as specific subunits and IL12p40 peptide as a common subunit [7]. IL23 is essential for the differentiation of Th17 lymphocytes and for the production of pro-inflammatory cytokines such as IL1, IL6 and TNF-alpha, while IL12 induces Th1 cell differentiation which has protective role in autoimmune responses [8]. IL23 signals through a heterodimeric receptor complex made of IL23R and IL12Rβ1 subunits. IL23Rβ1 peptide is also part of the IL12 receptor, while IL23R is specific for the IL23 receptor [9].
Several single nucleotide polymorphisms (SNPs) in the genes coding for members of IL12/23 axis have been found to be associated with the susceptibility to various immune-mediated diseases, namely SNPs in IL23R with ankylosing spondylitis and inflammatory bowel disease [10], [11] and in IL12B and IL23R with psoriasis [12]. Recent studies have shown that variations in IL12B (p40), IL23A (p19) and IL23R (IL23R) genes have been associated also with PsA in Caucasian populations [3], [4], [13], [14], [15]. Despite intensive research efforts, the pathological mechanisms of IL12 and IL23 cytokines involvement in immune-mediated diseases have not been yet elucidated.
The aim of this study was, therefore, to investigate a possible relationship of SNPs of the genes coding for IL12, IL23 and IL23R with susceptibility and clinical symptoms of PsA in Romanian population.
Section snippets
Subjects
The study group consisted of 94 Romanian unrelated consecutive PsA patients (42/52 male/female, mean age 51.5 years, range 23–86 years). The patients were assessed to fulfill the classification criteria for the diagnosis of psoriatic arthritis (CASPAR) [16] by an experienced rheumatologist (MB). Patients were classified at the time of study entry as having oligoarticular PsA (2–4 joints involved, 23 patients), polyarticular PsA (⩾5 joints involved, 40 patients) or axial disease (a history of
Association of studied SNPs in the genes coding for IL12, IL23 and IL23R with PsA
In order to assess a genetic association between 25 SNPs in 5 genes coding for IL12, IL23 and IL23R and susceptibility to PsA, 94 patients with PsA and 161 healthy control subjects, all unrelated Caucasians of Romanian origin, were genotyped using Sequenom MassARRAY platform (Table 1 and Fig. 1). The SNP rs11209026 was genotyped simultaneously by a second method, allelic discriminating Real-time PCR using TaqMan SNP Genotyping Assay. The results showed 100% concordance between these two
Discussion
Recent advances in the genetics and treatment of PsA have highlighted the implication of IL12 and IL23 in the pathology of this condition. To shed more light on IL12/23 in PsA, twenty five SNPs from five genes involved in IL12/23 signaling were genotyped in order to search for associations with the susceptibility and clinical subtypes of psoriatic arthritis in the Romanian population. This is the first study of IL12/23 coding genes in a Romanian case-control cohort.
Disclosure statement
The authors declare that they have nothing to disclose.
Author contributions
OMP and MP had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of data analysis. Study design: OMP, EK, MP. Data acquisition and analysis: OMP, EK, PS, MID, MB, CB. Statistical analysis: OMP, LP. Data interpretation and final approval of the manuscript: OMP, EK, LP, PS, MID, MB, CB, MP. Manuscript preparation: OMP, EK, LP, MP. Revision: OP, MP, EK, LP, MB. Study coordination and management: MP. All authors read and approved the
Acknowledgements
This study was supported by CZ 1.05/2.1.00/01.0030 Grant, Czech Republic and by PNII-IDEI 311/2007 Project, Romania.
References (36)
- et al.
Guidelines of care for the management of psoriasis and psoriatic arthritis: section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics
J Am Acad Dermatol
(2008) - et al.
Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12
Immunity
(2000) - et al.
The IL-23/Th17 axis in the immunopathogenesis of psoriasis
J Invest Dermatol
(2009) - et al.
Genetic variations in cytokines and cytokine receptors associated with psoriasis found by genome-wide association
J Invest Dermatol
(2009) - et al.
Genetic variants of the IL-23R pathway: association with psoriatic arthritis and psoriasis vulgaris, but no specific risk factor for arthritis
J Invest Dermatol
(2009) - et al.
PLINK: a tool set for whole-genome association and population-based linkage analyses
Am J Hum Genet
(2007) - et al.
Contrasting linkage-disequilibrium patterns between cases and controls as a novel association-mapping method
Am J Hum Genet
(2006) - et al.
The Th17/IL-23 axis and natural immunity in psoriatic arthritis
Int J Rheumatol
(2012) - et al.
Confirmation of TNIP1 and IL23A as susceptibility loci for psoriatic arthritis
Ann Rheum Dis
(2011) - et al.
Exploring ankylosing spondylitis-associated ERAP1, IL23R and IL12B gene polymorphisms in subphenotypes of psoriatic arthritis
Rheumatology (Oxford)
(2013)
In vitro and in situ expression of IL23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin
J Immunol
Ustekinumab: a review in the treatment of plaque psoriasis and psoriatic arthritis
J Drugs Dermatol
Interleukin-23: as a drug target for autoimmune inflammatory diseases
Immunology
Interleukin-23 receptor genetic polymorphisms and ankylosing spondylitis susceptibility: a meta-analysis
Rheumatol. Int.
The IL23 axis plays a key role in the pathogenesis of IBD
Gut
Association of interleukin 23 receptor variants with psoriatic arthritis
J Rheumatol
Investigation of association of the IL12B and IL23R genes with psoriatic arthritis
Arthritis Rheum
Classification criteria for psoriatic arthritis: development of new criteria from a large international study
Arthritis Rheum
Cited by (16)
Association with Genetic Variants in the IL-23 and NF-κB Pathways Discriminates between Mild and Severe Psoriasis Skin Disease
2015, Journal of Investigative DermatologyCitation Excerpt :This study describes association with genes in the IL-23 and NF-κB pathways in carefully characterized Swedish psoriasis cohorts stratified by severity of the skin phenotype. Several studies have previously highlighted the importance of genes and haplotypes in both the IL-23 and NF-κB pathways in psoriasis (Nair et al., 2009; Safrany et al., 2011; Safrany et al., 2013) as well as in many other immune-mediated diseases: PsA (Cargill et al., 2007; Capon et al., 2007; Liu et al., 2008; Nair et al., 2010; Franke et al., 2010; Strange et al., 2010; Bowes et al., 2011; Wang et al., 2012; Di Meglio et al., 2013; Popa et al., 2013; Eiris et al., 2014), Crohn’s disease (Chua et al., 2012; Dinu et al., 2012; Jung et al., 2012), inflammatory bowel disease (Duerr et al., 2006; Safrany et al., 2013), ankylosing spondylitis (Safrany et al., 2009), celiac disease, and multiple sclerosis (Nunez et al., 2008). The present study revealed that eight SNPs in six of the studied genes associate with psoriasis with a severe phenotype, whereas no association was found in patients with a consistent mild phenotype (Figure 1).
The 3'UTR 1188A/C polymorphism of IL-12p40 is not associated with susceptibility for developing plaque psoriasis in Mestizo population from western Mexico
2015, Immunology LettersCitation Excerpt :To our knowledge, this is the first and only study performed in Mexican Mestizo population from western Mexico, in which the association of rs3212227 with susceptibility for plaque psoriasis and with serum levels of IL-12 and IL-23. In our study, we showed that is no association between the 3′UTR 1188 A/C polymorphism of IL-12p40 and plaque psoriasis in Mestizo population of western Mexico (p = 0.747), which coincides with that reported in other studies conducted in Caucasian population with psoriasis [39,40] and psoriatic arthritis [41]. It also is in agreement with other works in which the association has been studied of SNP rs3212227 with other autoimmune diseases, such as Crohn's disease [42], rheumatoid arthritis [43], autoimmune thyroiditis [44] and systemic lupus erythematosus [45].
Genetic variants of the IL22 promoter associate to onset of psoriasis before puberty and increased IL-22 production in T cells
2014, Journal of Investigative DermatologyCitation Excerpt :The majority of identified psoriasis susceptibility genes are involved in the immune system. The activation of T-helper 17 (Th17) is currently in focus and is underscored by the genetic association to components in the Th17 pathway such as interleukin 23 receptor (IL23R), IL12B, and IL23A (Capon et al., 2007; Nair et al., 2010; Di Meglio et al., 2011; Wang et al., 2012; Popa et al., 2013), and by the compelling efficacy of therapies targeting this pathway. IL-22 is highly expressed by immune cells such as T cells in several chronic inflammatory conditions, including psoriasis (Zheng et al., 2007; Pan et al., 2013).
Genetic variations in IL6 and IL12B decreasing the risk for psoriasis
2013, Immunology LettersCitation Excerpt :IL-6 appears to be involved at different key points of psoriasis pathogenesis, like in the Th17 cells development from naive T cells, or in the IL-23-induced skin inflammation, that cannot occur in its absence [17,18]. Genome wide association studies have identified more than 30 psoriasis susceptibility loci (PSORS) [19–21], many of these being located in genes involved in psoriasis immunopathogenesis (e.g. IL12B, IL23R), harboring single nucleotide polymorphisms (SNPs) associated with increased risk of developing psoriasis. While the relative role of these polymorphisms in increasing the risk for psoriasis has been confirmed by several studies, little is known about the protective role of their genetic variants.
Comments on “Effect of polymorphisms in the IL-12B p40, IL-17A and IL-23 A/G genes on the response of psoriatic patients to narrowband UVB”
2021, Photodermatology Photoimmunology and Photomedicine
- 1
These authors contributed equally to this work.