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Peptidylarginine deiminases (PADs) catalyze citrullination, a post-translational modification playing a pathogenic role in anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA). The interplay between single nucleotide polymorphisms (SNPs) in the  PADI  genes and known risk factors for ACPA-positive RA, including smoking, HLA-DR4 and -1, and the PTPN22 R620W polymorphism, was investigated. We typed four  PADI2  SNPs, four  PADI4  SNPs, and the PTPN22 R620W SNP in 445 Danish RA patients and 533 age-matched healthy controls, as well as in 200 North American RA patients and 100 age- and sex-matched controls. The  HLA-DRB1  locus was typed in the Danish cohort. Logistic regression analyses, adjusted for age, sex, smoking status, and PTPN22 R620W, revealed increased risk of anti-CCP-positive RA in carriers of rs11203367(T) (OR: 1.22, p=0.03) and reduced risk in carriers of rs2240335(A) in  PADI4  (OR: 0.82, p=0.04). rs74058715(T) in  PADI4  conferred reduced risk of anti-CCP-negative RA (OR: 0.38, p=0.003). In  HLA-DRB1*04 -positive individuals, specifically, the risk of anti-CCP-positive RA was increased by carriage of  PADI4  rs1748033(T) (OR: 1.54, p=0.007) and decreased by carriage of  PADI4  rs74058715(T) (OR: 0.44, p=0.01), and we observed an interaction between these SNPs and  HLA-DRB1*04  (p=0.004 and p=0.008, respectively) Thus,  PADI4  polymorphisms associate with ACPA-positive RA, particularly in  HLA-DRB1*04 -positive individuals, and with ACPA-negative RA independently of  HLA - DRB1*04 .

PADI4 Polymorphisms Confer Risk of Anti-CCP-Positive Rheumatoid Arthritis in Synergy With HLA-DRB1*04 and Smoking