Association of Anti–Cyclic citrullinated peptide antibody levels with PADI4 haplotypes in early rheumatoid arthritis and with shared epitope alleles in very late rheumatoid arthritis

OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies 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 peptidyl arginine deiminase 4 gene (PADI4). This study was undertaken to determine whether anti-CCP levels are associated with PADI4 haplotypes and/or SE alleles in Korean patients with RA. METHODS: 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 with nonerosive or erosive RA. The relationships between anti-CCP levels and PADI4 haplotypes and/or SE alleles were analyzed statistically. RESULTS: Anti-CCP levels were significantly higher in patients carrying the PADI4 RA risk haplotype than in patients who did not have the risk haplotype, among anti-CCP-positive patients with RA with a disease duration of or=141 months (P = 0.0037) and among those who had erosive RA (P = 0.000098), but not among patients who had a shorter disease duration or those who had nonerosive RA. CONCLUSION: The PADI4 RA risk haplotype is associated with increased anti-CCP levels in RA patients with disease of short duration, and PADI4 may play a role in early RA. In contrast, SE alleles are associated with increased anti-CCP levels in RA patients with very longstanding disease and in patients with erosive RA, suggesting that SE alleles play a role in very late RA.