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 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.
Highlights
Peptidylarginine deiminases (PADs) catalyze the post-translational conversion of peptidylarginine to peptidylcitrulline
The North American cohort had a median age of 63 years, which was higher than the 53 years of the Danish cohort, and it contained more women than the Danish cohort, within the anti-cyclic citrullinated peptide (CCP)-negative rheumatoid arthritis (RA) and healthy control groups
We found that none of the PADI2 single nucleotide polymorphism (SNP) included in this study associated with anti-CCP-positive or anti-CCP-negative RA (Table 2)
Summary
Peptidylarginine deiminases (PADs) catalyze the post-translational conversion of peptidylarginine to peptidylcitrulline. ACPAs, routinely detected using the anti-cyclic citrullinated peptide (anti-CCP) test [5], are often present years before clinically overt disease [6], and antiCCP-positive RA patients have a worse prognosis with a higher degree of erosive damage than anti-CPP-negative RA patients [7]. ACPA-positive RA is strongly associated with HLA molecules containing the so-called shared epitope (SE), which are capable of binding certain citrullinated peptides [8,9,10]. The shared epitope is present in most HLA-DRB1*04 subtypes (HLADRB1*0401, HLA-DRB1*0404, HLA-DRB1*0405, and HLADRB1*0408 but not in HLA-DR4B1*0402) and HLA-DRB1*01 subtypes (HLA-DRB1*0101 and HLA-DRB1*0102). HLA-DRB1*04, which is carried by 67–78% of anti-CCPpositive RA patients [10,11,12], correlates more strongly with anti-CCP-positive RA than HLA-DRB1*01 (reported in 22– 51% of anti-CCP-positive RA patients) [10,11,12]. The R620W variant of protein tyrosine phosphatase, nonreceptor type 22 (PTPN22), confers increased risk of ACPApositive RA [13, 14], as does smoking [9]
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