INVESTIGATION OF CANDIDATE GENE POLYMORPHISMS IN AN IMMUNE RESPONSE AS MARKERS FOR THE RISK OF DEVELOPING RHEUMATOID ARTHRITIS AND PRODUCING AUTOANTIBODIES

Abstract

Objective: to investigate the distribution of the genotypes and alleles of the PTPN22, TNFAIP3, CTLA4, TNFA, IL6, IL6R, IL10, MCP1, and ICAM1 genes in patients with rheumatoid arthritis (RA) and in the control group of healthy individuals, to estimate their significance as molecular genetic markers for predisposition to RA; and to analyze the correlation between the gene polymorphisms included in the study and the production of anti-cyclic citrullinated peptide antibodies (ACCPA) and IgM rheumatoid factor (RF).Subjects and methods. The investigation was conducted within the framework of the «Early arthritis: Diagnosis, outcome, criteria, active treatment program». The prospective follow-up study included 122 patients with RA fulfilling the 1987 American College of Rheumatology (ACR) criteria; with disease duration of ≤ 2 years. 73 (59.8%) patients were included during the first 6 months after the onset of the disease. 74 (60.7%) and 81 (66.5%) patients were found to be positive for ACCPA and IgM RF, respectively. 314 healthy blood donors served as a control group. A real-time polymerase chain reaction was used in the patients and control individuals to study the distribution of the polymorphic variants of PTPN22 (+1858 C >T, rs2476601), TNFAIP3 (rs675520, rs6920220, rs10499194), CTLA4 (+49A>G, rs231775 ), TNFА (-308A>G, rs1800629), IL6 (-174G>C, rs1800795), IL6R (+358A>C, rs8192284), IL10 (-592A>C, rs1800872, -1082 A>G, rs1800896), MCP1/CCL2 (+2518A>G, rs1024611), and ICAM1 (721G>A, rs1799969) genes. Results and discussion. This analysis revealed an association of PTPN22 (+1858 C >T, rs2476601) and TNFAIP3 (rs675520, rs10499194) polymorphisms with the risk of RA (odds ratio (OR), 1.5; 95% confidence interval (CI), 1.0–2.3; p = 0.05; OR, 1.5; 95% CI, 1.1–2.0; p = 0.02; OR, 0.5; 95% CI, 0.4–0.8; p = 0.01, respectively. Further, there was a tendency towards a positive association of TNFAIP3 (rs6920220) and IL6R (rs8192284) polymorphisms with a predisposition to RA (p = 0.056). IL6 (rs1800795), IL10 (rs1800872, rs1800896), MCP1/CCL2 (rs1024611), and ICAM1 (rs1799969) polymorphisms were not associated with the risk of RA. An analysis of the findings after patient stratification by ACCPA and IgM RF (a binary variable) showed that none of the polymorphisms in question was associated with RF state. At the same time, PTPN22 (rs2476601), TNFAIP3 (rs675520), TNFAIP3 (rs10499194), and TNFА (rs1800629) polymorphisms were found to be significantly related to ACCPA state (a binary variable). The level of ACCPA as a quantitative variable was statistically significantly associated with CTLA4 (rs231775) and TNFА (rs1800629) polymorphisms in a dose-dependent fashion (р = 0.025 and р = 0.015, respectively). There was a marked tendency towards an association of ACCPA levels and IL6R gene polymorphism (p = 0.07). IL6 (rs1800795), IL10 (rs1800872, rs1800896), MCP1/CCL2 (rs1024611), and ICAM1 (rs1799969) polymorphisms were not correlated with ACCPA state (binary and quantitative variables).Conclusion. The findings suggest that a number of genes are implicated in the pathogenesis of RA and that they are involved in the development of ACCPA-positive and ACCPA-negative RA subtypes. No relationship was found between the production of IgM RF and the polymorphisms of the genes under study. The findings suggest that there appears to be different mechanisms for the formation of autoantibodies (ACCPA and IgM RF) in RA.

Keywords

• early rheumatoid arthritis
• gene polymorphisms
• single-nucleotide polymorphism
• anti-cyclic citrullinated peptide antibodies
• rheumatoid factor