Interleukin-6 levels and their haplotypes are associated with serological autoantibodies status and clinical activity in rheumatoid arthritis

Ma. Natividad Flores-Castro¹Ramcés Falfán-Valencia²Olivia Briceño²Ilse Adriana Gutiérrez-Pérez¹Oscar Zaragoza-García¹Gloria Pérez-Rubio²Cristina Morales-Martínez³Iris Paola Guzmán-Guzmán^4*

• ¹Universidad Autonoma de Guerrero, Chilpancingo, Mexico
• ²Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
• ³Hospital General de Cuernavaca Doctor Jose G Parres, Cuernavaca, Mexico
• ⁴Autonomous University of Guerrero, Chilpancingo, Mexico

Interleukin 6 (IL-6) plays an important role in the pathogenesis, progression, and severity of rheumatoid arthritis (RA). High levels of IL-6 are involved in the maintenance of inflammation in the synovium, and the development of new blood vessels in the inflamed synovium, contributing to pannus formation. In the present study, we aimed to investigate the relationship of IL-6 polymorphisms/haplotypes with RA in Mexican patients and on circulating levels of IL-6 and the clinical features of the disease. 225 RA patients and 362 healthy controls were recruited. Patients' clinical features were collected, and inflammatory and serological parameters (anti-cyclic citrullinated peptides (anti-CCPs) and rheumatoid factor (RF) were assessed. All subjects were genotyped for IL-6 polymorphisms (rs1800797, rs1800796, and rs1818879) using real-time PCR with TaqMan probes. Circulating levels of IL-6 were measured by commercial ELISA kits. Our results show that GGG haplotype of the IL-6 gene is associated with a serological status of double-positive autoantibodies (OR = 2.09, p = 0.009), as well as with a double-positive high autoantibodies status (OR=2.08, p=0.04), although a marginal association was shown to RA susceptibility (OR = 1.34, p = 0.050). Polymorphisms and haplotypes were not associated with serum levels of IL-6. However, serum levels of IL-6 ≥27.6 pg/mL were associated with clinical features of RA severity, such as; morning stiffness ≥30 minutes (OR = 1.83, p = 0.001), HAQ-DI ≥1 (OR = 2.73, p = 0.009), DAS28-ESR ≥3.2 (OR = 3.63, p = 0.002), and hsCRP ≥10 mg/L (OR = 6.35, p <0.001). This study provides evidence of the relationship between IL-6 haplotypes, circulating levels of IL-6, and clinical features and serological status to autoantibodies in RA patients from Mexico.