PADI4 Polymorphisms Confer Risk of Anti-CCP-Positive Rheumatoid Arthritis in Synergy With HLA-DRB1*04 and Smoking
Abstract
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 thePADIgenes and known risk factors for ACPA-positive RA, including smoking, HLA-DR4 and -1, and the PTPN22 R620W polymorphism, was investigated. We typed fourPADI2SNPs, fourPADI4SNPs, 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. TheHLA-DRB1locus 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) inPADI4(OR: 0.82, p=0.04). rs74058715(T) inPADI4conferred reduced risk of anti-CCP-negative RA (OR: 0.38, p=0.003). InHLA-DRB1*04-positive individuals, specifically, the risk of anti-CCP-positive RA was increased by carriage ofPADI4rs1748033(T) (OR: 1.54, p=0.007) and decreased by carriage ofPADI4rs74058715(T) (OR: 0.44, p=0.01), and we observed an interaction between these SNPs andHLA-DRB1*04(p=0.004 and p=0.008, respectively) Thus,PADI4polymorphisms associate with ACPA-positive RA, particularly inHLA-DRB1*04-positive individuals, and with ACPA-negative RA independently ofHLA-DRB1*04.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 18, 2021
- Source ID
- 10.3389/fimmu.2021.707690
Entities
People
- Christian Enevold
- Claus Henrik Nielsen
- Dres Damgaard
- Laura Massarenti
- Miriam A. Shelef
- Morten Frisch
- Niels Ødum
- Peter Garred
- Søren Jacobsen
Organizations
- Congressionally Directed Medical Research Programs
- Danish Rheumatism Association
- Doris Duke Charitable Foundation
- Independent Research Fund Denmark
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- Novo Nordisk Fonden
- University of Wisconsin School of Medicine and Public Health