Genetic Background of Anticyclic Citrullinated Peptide Autoantibody Production in Hungarian Patients with Rheumatoid Arthritis

Abstract

Polymorphisms of the peptidylarginine deiminase 4 (PADI4) gene encoding for the isoenzyme that converts arginyl into citrullyl residues have been shown to contribute to susceptibility to rheumatoid arthritis (RA), depending on the population studied. We aimed at determining whether PADI4 single nucleotide polymorphisms (SNPs) are associated with RA in a Hungarian population. The relationship between anticyclic citrullinated peptide (anti-CCP) production and HLA-DRB1 alleles encoding the shared epitope (SE) was also investigated. DNA samples were obtained from RA (n = 261) patients and from control donors (n = 120). HLA-DRB1 genotyping was carried out by polymerase chain reaction (PCR) with sequence-specific priming. PAD4_92 G/C and PAD4_104 T/C SNPs were genotyped using real-time PCR allele discrimination. Autoantibodies against CCP were detected by ELISA. All healthy controls tested anti-CCP negative, whereas 171 (66%) RA patients were anti-CCP positive. No significant difference in allele or genotype frequencies were found between RA patients and controls for any of the PADI4 SNPs. Anti-CCP seropositivity was unrelated to these two SNPs. No association was found between any of the PADI4 SNPs and HLA-DRB1 subtypes. Presence of the HLA-RB1 SE alleles was significantly associated with anti-CCP seropositivity; HLA-DRB1*0401 and HLA-DRB1*1001 carriers showed the strongest association. In conclusion, our data suggest that polymorphisms of the PADI4 gene are not associated with rheumatoid arthritis and are unlikely to be responsible for the presence of anti-CCP autoantibodies in a white Hungarian population. HLA-DRB1 SE alleles, however, may significantly contribute to the genetic determination of anti-CCP production in Hungarian patients with RA.

Role of citrullination modification catalyzed by peptidylarginine deiminase 4 in gene transcriptional regulation

“…The role of PADI4 in early RA pathogenesis is mainly through promoting the generation of citrullinated autoantigens [57,58]. PADI4 has been identified as a new therapeutic target for RA treatment [59][60][61][62]. PADI4 is also overexpressed in the multiple sclerosis [63,64], and heterozygote genotypes for PADI4_89 were protectively associated with susceptibility to tuberculosis in Koreans [65]; however, the underlying mechanism remains unclear.…”

“…PADI4 is able to promote chromatin decondensation and DNA fragmentation [20,21]. Activation of PADI4 reduces heterochromatin and multilobular nuclear structures in HL- 60 Figure 1. Schematic representation of the major substrates and regulation mechanism of PADI4 PADI4 deiminates both histone proteins (shown in yellow) and non-histone proteins (shown in green).…”

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

“…Accordingly, a geneenvironment interaction between the shared epitope and smoking in ACPAϩ, but not ACPA-, RA has been reported in northern European RA patient cohorts (8,9). On the other hand, however, the association of the specific HLA-DRB1 alleles with ACPAϩ RA appears to vary between different populations (10)(11)(12), and the specific gene-environment interaction in ACPAϩ RA could not be confirmed in all studies (13,14).…”

Polymyalgia rheumatica update, 2015

“…A DR-asszociációk a PMR-fogékonyság mellett a betegség súlyosságával is összefüggnek. Saját vizsgálatunkban magyar populáción a DRB1*0401 szubtípus asszociációját szignifi kánsan alacsonyabbnak találtuk PMR-ben, mint RA-ban [12,13]. Ugyanakkor spanyolok a DRB1*0401 szubtípus súlyos, relapsusokkal járó PMR-rel való asszociációját ír-ták le.…”