(The) different associations of PADI4 haplotypes and HLA-DRB1 shared epitope alleles with anti-cyclic citrullinated peptide antibody levels in rheumatoid arthritis.

Abstract

Anti-cyclic citrullinated peptide antibodies (anti-CCPs) are rheumatoid arthritis (RA)-specific serologic markers. RA susceptibility has been associated with HLA-DRB1 shared epitope (SE) alleles and single-nucleotide polymorphism (SNP) haplotypes in the peptidylarginine deiminase 4 gene (PADI4). Here, we tested whether anti-CCP levels are associated with PADI4 haplotypes and/or SE alleles in Korean RA patients. Three nonsynonymous SNPs in PADI4 (padi4_89, padi4_90 and padi4_92) and SE alleles were genotyped, and serum anti-CCP levels were measured in 311 patients having non-erosive or erosive RA. The relationships between anti-CCP levels and PADI4 haplotypes and/or SE alleles were statistically examined. Anti-CCP levels were significantly higher in PADI4 RA-risk haplotype carriers versus non-carriers among anti-CCP-positive patients having non-erosive RA (P = 0.022, 2.0-fold in mean level) and among those afflicted with RA for 40 months or less (P = 0.019, 2.1-fold), but not among patients having erosive RA or afflicted longer. In contrast, the levels were significantly higher in SE carriers versus non-carriers among patients with erosive RA (P = 0.000098, 2.0-fold) and among those afflicted with RA for 122 months or more (P = 0.00059, 2.2-fold), but not among patients having non-erosive RA or afflicted shorter. Conclusively, the PADI4 RA-risk haplotype is associated with increased anti-CCP levels in non-erosive but not in erosive RA patients and PADI4 may play a role in early RA. In contrast, SE alleles are associated with increased anti-CCP levels in erosive but not in non-erosive RA patients and SE may play a role in very late RA.