Elsevier

Cytokine

Volume 63, Issue 1, July 2013, Pages 67-73
Cytokine

Association study in Romanians confirms IL23A gene haplotype block rs2066808/rs11171806 as conferring risk to psoriatic arthritis

https://doi.org/10.1016/j.cyto.2013.04.013Get rights and content

Highlights

  • We examined SNPs mapping to IL12/23 and IL23 receptor genes in psoriatic arthritis.

  • IL23A gene variations and haplotype were associated with lower risk of the disease.

  • Variants of IL12B gene were associated with polyarticular subtype of arthritis.

  • Data suggest a role for IL23 in the psoriatic arthritis pathogenesis in Romanians.

Abstract

Background

The cytokines IL12 and IL23 have been recently implicated in the pathogenesis of psoriatic arthritis (PsA). In this study we investigated the genetic variations in the genes coding for IL12, IL23 and IL23 receptor as a plausible source of susceptibility and modification of clinical symptoms of PsA in Romanian population.

Methods

Twenty five SNPs mapping to IL12A, IL12B, IL23A, IL23R and IL12RB1 genes were genotyped in 94 PsA patients and 161 healthy controls of Romanian ethnicity using the Sequenom genotyping platform.

Results

The exonic SNP rs11171806 from IL23A gene was significantly underrepresented in patients versus controls (p = 0.03, OR 0.391) and the carriers of rs11171806/rs2066808 AC haplotype had decreased risk for PsA (p = 0.03). The two SNPs of the highly conserved gene IL23A are in complete LD in our population. Genetic variants of IL12B gene were associated with polyarticular subtype of PsA. No associations were found between SNPs from IL12A, IL23R and IL12RB1 genes and susceptibility to PsA and its phenotypes.

Conclusion

We confirm the previously described association of rs2066808 variant with psoriasis and PsA and we show evidence of an extended genomic region inside IL23A gene as carrier of true disease susceptibility factors. These data suggest a role for IL23 in the PsA pathogenesis in Romanians.

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.

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