Contribution OF Non-HLA Genes to Juvenile Idiopathic Arthritis Susceptibility

Juvenile idiopathic arthritis (JIA) is a multifactorial immune-mediated inflammatory disease in childhood, the most common type of rheumatic disease in children. It is characterized by the polygenic type of hereditary predisposition.Objective: to study the association of STAT4 rs7574865 G/T and IRF5 rs2004640 G/T polymorphisms with the predisposition to certain JIA subtypes in the Russian pediatric population.Patients and methods. The investigation enrolled 177 patients, including 66 patients diagnosed with JIA and 111 healthy unrelated volunteers (a control group). Of the 66 patients with JIA there were 30 (45%) with oligoarthritis: 20 (67%) with human leukocyte antigen B27(HLA-B27)-positive JIA (that was associated with enthesitis, HLA-B27 positive JIA (JIA-B27), 10 (33%) with anterior uveitis concurrent with antinuclear antibody-positive JIA (JIA-uveitis); 20 (30%) with polyarticular JIA (JIA-poly), seronegative for rheumatoid factor; and 16 (24%) with systemic JIA (JIA-sys). As a control for genotyping STAT4 rs7574865 G/T and IRF5 rs2004640 G/T polymorphisms, the investigators studied 103 and 111 DNA samples from healthy adult volunteers, respectively. STAT4 rs7574865 G/T and IRF5 rs2004640 G/T polymorphisms were investigated using allele-specific real-time polymerase chain reaction (RT-PCR).Results and discussion. In the oligoarticular JIA group, the frequency of the STAT4 T allele was significantly higher than that in the control group (38.3 and 20.4%, respectively; p=0.004). This allele was also significantly more common in the JIA-B27 (35.0 and 20.4%, respectively; p=0.044) and JIA-uveitis (45.0 and 20.4%, respectively; p=0.021) groups compared with the control one. No significant differences were found in the frequency of the mutant STAT4 T allele between the control group and the JIA-sys and JIA-poly groups. Regression analysis showed that the identification of the STAT4 T allele was associated with the high risk of a predisposition to oligoarticular JIA as a whole (odds ratio, OR 2.43; 95% confidence interval (CI) 1.23–4.70; p=0.007), as well as to the antinuclear antibody-positive oligoarticular JIA with uveitis (JIA-uveitis): the risk in T allele carriers was 3.2 times higher than that in the control (OR 3.19; 95% CI 1.09–9.06; p= ). A high risk for predisposition was also found in the JIA-B27 subgroup compared with the control (OR 2.10; 95% CI 0.38–4.60; p=0.070). There were no statistical differences in the frequency of genotypes and alleles of the IRF5 rs2004640 G/T polymorphism between the entire group of JIA as a whole and its individual clinical types, as well as the control group.Conclusion. This pilot study confirmed that the STAT4 rs7574865 G/T polymorphism was associated with the risk of oligoarticular JIA, mainly that of JIA-uveitis and JIA-B27.

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STAT4 rs7574865 G/T and IRF5 rs2004640 G/T polymorphisms as markers of predisposition to juvenile idiopathic arthritis. What can genetics give to understand its heterogeneity?

Фёдоров¹,

Крылов²,

Салугина³

et al. 2019

Sovremennaâ revmatologiâ

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Relationship of genetic polymorphism of the acute phase marker of inflammation rs12218 of the SAA1 gene with clinical phenotypes of juvenile idiopathic arthritis

Krylov¹,

Fedorov²,

Салугина³

2021

Sovremennaâ revmatologiâ

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Objective: to test the hypothesis of a possible relationship between the rs12218 polymorphism of the SAA1 gene and a predisposition to different clinical phenotypes of juvenile idiopathic arthritis (JIA).Patients and methods. Genetic typing of rs12218 polymorphism was carried out in 142 children: 77 of them were diagnosed with JIA, including 30 patients with oligoarthritis (oJIA), 20 with polyarthritis (pJIA), and 27 with systemic onset (sJIA). Sixty five healthy volunteers were included in the control group. The rs12218 polymorphism of the SAA1 gene was investigated using real-time polymerase chain reaction.Results and discussion. A high risk of developing the clinical phenotype of oJIA in carriers of the C mutant allele of the rs12218 T/C polymorphism of the SAA1 gene was established. Statistically significant differences between the clinical phenotypes of oJIA and sJIA in the frequency distribution of genotypes and alleles of rs12218 T/C polymorphism of the SAA1 gene are shown.Conclusion. The results of the studies have confirmed the important role of the rs12218 T/C polymorphism of the SAA1 gene in the formation of susceptibility to clinical variants of JIA.

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Cytokine status and hemostasis disorders in children with juvenile idiopathic arthritis

Gomellya,

Mironova,

Krupskaya

et al. 2024

Acta biomedica scientifica

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Juvenile idiopathic arthritis is a chronic inflammatory joint disease in children under 16 years of age associated with pathological immune response to various antigens. Probable factors are infectious and immunogenetic. The process begins with the activation of humoral immunity. One of the key components of juvenile idiopathic arthritis pathogenesis is damage to the vascular endothelium. Immune complex vasculitis develops with hemostasis and microcirculation disorders in synovial membrane. Proinflammatory cytokines are produced, causing the destruction of the synovial membrane of the joint, cartilage, bone, contributing to the chronicity of the inflammatory process. In patients with rheumatic diseases, hemostatic changes occur in 4.5–63 % of cases, especially with high activity of the inflammatory process. In juvenile idiopathic arthritis, hemostasis disorders include thrombinemia, decreased antithrombin III, increased D-dimer level, and decreased fibrinolysis activity. Thrombodynamics test in adults with rheumatoid arthritis has shown the presence of a chronic hypercoagulable state. Rheumatoid arthritis is a risk factor for thrombotic complications in adults. There are no data on the study of thrombodynamic parameters in juvenile idiopathic arthritis. Currently, the pathogenetic commonality between autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and immune-mediated antiphospholipid syndrome is known. The mechanisms of development of antiphospholipid syndrome are associated with an imbalance in the hemostasis system under the influence of autoantibodies to phospholipids of cell membranes, which can interact with endothelial cells, various components of the coagulation system, causing thrombotic complications. The importance of studying immune-mediated antiphospholipid syndrome in juvenile idiopathic arthritis is beyond doubt, but data on this issue in the pediatric population are extremely limited, including the relationship of antiphospholipid syndrome with immune hemostasis parameters. Single studies of immune-mediated antiphospholipid syndrome in children with juvenile idiopathic arthritis indicate that antiphospholipid syndrome markers are found in all variants of juvenile idiopathic arthritis, although thrombotic complications are rare.

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Contribution OF Non-HLA Genes to Juvenile Idiopathic Arthritis Susceptibility

Abstract: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatologic disease in children. JIA is a group of disorders that share the clinical manifestation of chronic joint inflammation. The Human Leukocyte Antigen region (HLA) (Вестник РАМН. 2014; 9-10: 83-94)

Cited by 3 publications

References 74 publications

<i>STAT4</i> rs7574865 G/T and <i>IRF5</i> rs2004640 G/T polymorphisms as markers of predisposition to juvenile idiopathic arthritis. What can genetics give to understand its heterogeneity?

<i>STAT4</i> rs7574865 G/T and <i>IRF5</i> rs2004640 G/T polymorphisms as markers of predisposition to juvenile idiopathic arthritis. What can genetics give to understand its heterogeneity?

Relationship of genetic polymorphism of the acute phase marker of inflammation rs12218 of the SAA1 gene with clinical phenotypes of juvenile idiopathic arthritis

Cytokine status and hemostasis disorders in children with juvenile idiopathic arthritis

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