AUTHOR=Massarenti Laura , Enevold Christian , Damgaard Dres , Ødum Niels , Garred Peter , Frisch Morten , Shelef Miriam A. , Jacobsen Søren , Nielsen Claus Henrik 

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

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.707690

DOI=10.3389/fimmu.2021.707690

ISSN=1664-3224

ABSTRACT=<p>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 <italic>PADI</italic> 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 <italic>PADI2</italic> SNPs, four <italic>PADI4</italic> 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 <italic>HLA-DRB1</italic> 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 <italic>PADI4</italic> (OR: 0.82, p=0.04). rs74058715(T) in <italic>PADI4</italic> conferred reduced risk of anti-CCP-negative RA (OR: 0.38, p=0.003). In <italic>HLA-DRB1*04</italic>-positive individuals, specifically, the risk of anti-CCP-positive RA was increased by carriage of <italic>PADI4</italic> rs1748033(T) (OR: 1.54, p=0.007) and decreased by carriage of <italic>PADI4</italic> rs74058715(T) (OR: 0.44, p=0.01), and we observed an interaction between these SNPs and <italic>HLA-DRB1*04</italic> (p=0.004 and p=0.008, respectively) Thus, <italic>PADI4</italic> polymorphisms associate with ACPA-positive RA, particularly in <italic>HLA-DRB1*04</italic>-positive individuals, and with ACPA-negative RA independently of <italic>HLA</italic>-<italic>DRB1*04</italic>.</p>