Abstract
Protein citrullination is carried out by peptidylarginine deiminase type 4 (PAD4) enzyme. As a consequence of this process, post-translationally modified proteins are formed that become antigens for anti-citrullinated protein antibodies (ACPA). The study aimed at identifying whether the PADI4 gene is subject to epigenetic regulation through methylation of its promoter region, whether the degree of methylation differs in healthy individuals vs. rheumatoid arthritis (RA) patients and changes in correlation with ACPA, anti-PAD4 and disease activity. A total of 125 RA patients and 30 healthy controls were enrolled. Quantitative real-time methylation-specific PCR was used to analyze the methylation status. ACPA and anti-PAD4 antibodies were determined in serum by enzyme-linked immunosorbent immunoassay. The differences were observed in the degree of PADI4 gene promoter methylation between RA patients and HC, along with an upward trend for the methylation in RA, which was inversely proportional to the disease activity. A weak or modest negative correlation between the degree of PADI4 gene methylation and anti-PAD4, disease activity score (DAS28) and ACPA level has been found. The elevated methylation is associated with lower disease activity, lower levels of ACPA and aPAD4. The methylation degree in this area is growing up during effective treatment and might play a role in the RA pathophysiology and therefore could be a future therapeutic target.
Highlights
Rheumatoid Arthritis (RA) is a chronic, progressive, autoimmune inflammatory disease affecting various organs and tissues, predominantly the synovial membrane, leading to joint destruction [1]
We have presented a novel finding indicating that the PADI4 gene undergoes epigenetic regulation through methylation of its promoter region
An increase in methylation in this area is associated with lower levels of anti-peptidylarginine deiminase type 4 (PAD4) and Anti-citrullinated protein antibodies (ACPA) and with lower disease activity
Summary
Rheumatoid Arthritis (RA) is a chronic, progressive, autoimmune inflammatory disease affecting various organs and tissues, predominantly the synovial membrane, leading to joint destruction [1]. Starting from 2010, along with rheumatoid factor (RF), ACPA are used as serological markers according to the classification criteria of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) [2]. Their sensitivity and specificity for the diagnosis of RA are 64.9% and 97.9%, respectively [3]. The first consists of 663 amino acids (aa) and molecular weight 74.1 kDa, the second one 127 aa and 13.1 kDa [8]
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