PADI4 Polymorphisms Confer Risk of Anti-CCP-Positive Rheumatoid Arthritis in Synergy With HLA-DRB1*04 and Smoking
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PADI4 Polymorphisms Confer Risk of Anti-CCP-Positive Rheumatoid Arthritis in Synergy With HLA-DRB1*04 and Smoking. / Massarenti, Laura; Enevold, Christian; Damgaard, Dres; Ødum, Niels; Garred, Peter; Frisch, Morten; Shelef, Miriam A.; Jacobsen, Søren; Nielsen, Claus Henrik.
In: Frontiers in Immunology, Vol. 12, 707690, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - PADI4 Polymorphisms Confer Risk of Anti-CCP-Positive Rheumatoid Arthritis in Synergy With HLA-DRB1*04 and Smoking
AU - Massarenti, Laura
AU - Enevold, Christian
AU - Damgaard, Dres
AU - Ødum, Niels
AU - Garred, Peter
AU - Frisch, Morten
AU - Shelef, Miriam A.
AU - Jacobsen, Søren
AU - Nielsen, Claus Henrik
N1 - Publisher Copyright: © Copyright © 2021 Massarenti, Enevold, Damgaard, Ødum, Garred, Frisch, Shelef, Jacobsen and Nielsen.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - anti-citrullinated proteins antibodies (ACPA)
KW - HLA-DRB104
KW - peptidylarginine deiminase (PAD)
KW - rheumatoid arthritis
KW - single nucleotide polymorphism (SNP)
U2 - 10.3389/fimmu.2021.707690
DO - 10.3389/fimmu.2021.707690
M3 - Journal article
C2 - 34733271
AN - SCOPUS:85118322187
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 707690
ER -
ID: 284700571