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

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

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.

OriginalsprogEngelsk
Artikelnummer707690
TidsskriftFrontiers in Immunology
Vol/bind12
ISSN1664-3224
DOI
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
This study was provided by the Independent Research Fund, Denmark (grant number DFF - 7016-00233) to CN as well as from the University of Wisconsin School of Medicine and Public Health from the Wisconsin Partnership Program (grant number 2951) and the Doris Duke Charitable Foundation (grant number

Publisher Copyright:
© Copyright © 2021 Massarenti, Enevold, Damgaard, Ødum, Garred, Frisch, Shelef, Jacobsen and Nielsen.

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