PADI2 Polymorphisms Are Significantly Associated With Rheumatoid Arthritis, Autoantibodies Serologic Status and Joint Damage in Women from Southern Mexico

Abstract

The enzymes of the family peptidylarginine deiminases (PADs) have an important role in the pathogenesis of rheumatoid arthritis (RA) due to their association with the anti-citrullinated protein antibodies (ACPA) production. To evaluate the association between single-nucleotide polymorphisms (SNPs) in the PADI2 gene and RA susceptibility, related clinical parameters, and the serologic status of autoantibodies in a women population with RA from southern Mexico, a case-control study was conducted (case n=229; control n=333). Sociodemographic characteristics were evaluated, along with clinical parameters, inflammation markers, the levels of ACPAs as anti-cyclic citrullinated peptides (anti-CCPs), anti-modified citrullinated vimentin (anti-MCV), and rheumatoid factor (RF). Genomic DNA was extracted from peripheral blood, and three SNPs of the PADI2 gene (rs1005753, rs2057094, and rs2235926) were performed by qPCR using TaqMan probes. The data analysis reveals that the carriers of the T allele for rs2057094 and rs2235926 presented an earlier onset of the disease (β= -3.26; p = 0.03 and β = -4.13; p = 0.015, respectively) while the carriers of the T allele for rs1005753 presented higher levels of anti-CCPs (β= 68.3; p = 0.015). Additionally, the T allele of rs2235926 was associated with a positive RF (OR = 2.90; p = 0.04), anti-MCV (OR = 2.92; p = 0.05), and with the serologic status anti-CCP+/anti-MCV+ (OR = 3.02; p = 0.03), and anti-CCP+/anti-MCV+/RF+ (OR = 3.79; p = 0.004). The haplotypes GTT (OR =1.52; p = 0.027) and TTT (OR = 1.32; p = 0.025) were associated with the presence of RA. In addition, in this study the haplotype TTT is linked to the presence of radiographic joint damage defined by a Sharp-van der Heijde score (SHS) ≥2 (OR = 1.97; p = 0.0021) and SHS ≥3 (OR = 1.94; p = 0.011). The haplotype TTT of SNPs rs1005753, rs2057094, and rs2235926 of the PADI2 gene confers genetic susceptibility to RA and radiographic joint damage in women from southern Mexico. The evidence reveals that SNPs of the PADI2 gene favors the presence of a positive serologic status in multiple autoantibodies and the clinical manifestations of RA at an early onset age.

Altered Transcriptional Regulation of Glycolysis in Circulating CD8+ T Cells of Rheumatoid Arthritis Patients

“…Among the transcription factors, SPI1 , PADI2 , ZNF366 and CBFA2T3 were in the top ten transcription factors for hub score, betweenness centrality and out-degrees for all the comparisons. Polymorphisms in the PADI2 genes are associated with RA [ 33 , 34 ]. Its role in circulating CD4 + T cells of RA patients is unknown.…”

Anti-citrullinated α-enolase peptide as a highly sensitive autoantigen in patients with rheumatoid arthritis

“…In RA diagnosis, composite scores of disease activity, such as the DAS-28 (including tender joint count (TJC) and swollen joint count (SJC)), along with the measurement of ESR, CRP level, and general health (GH) status are of importance in evaluating RA treatment response. However, the assessment of these parameters in groups of patients may not be as accurate as that in individual patients [ 34 ]. In the present study, patients with RA exhibited high disease activity with a moderately elevated inflammatory condition based on the DAS-28, ESR, and GH status, whereas the CRP level remained normal.…”

“…Furthermore, the anti-CEP was notably associated with the PADI2 SNP rs1005753 ( **p < 0.01). Moreover, PADI2 has been found to be a candidate gene in RA progression, and its high expression has been observed in the synovial fluid of patients with RA, correlating with inflammatory markers and clinical activity of the disease [ [46] , [47] , [48] ]. In addition, Too et al identified a novel association between the PADI2 genetic variant rs1005753 and RA in a multiethnic population from Southeast Asia [ 49 ].…”

Role of the PADI family in inflammatory autoimmune diseases and cancers: A systematic review

“…This causes the destruction of cartilage and the aggravation of RA ( 94 ). Furthermore, individual genetic polymorphisms of PADI2 and PADI4 can increase susceptibility to RA ( 35 – 37 , 41 , 43 , 46 , 47 , 95 – 97 ). In ACPA RA, PADI4 can help HLA-DRB1 bind to ACPA ( 98 , 99 ).…”