Abstract
Peptidylarginine deiminase type 4 (PADI4) genotypes were shown to influence susceptibility to rheumatoid arthritis (RA) in the Japanese population. Such an association could not previously be confirmed in different European populations. In the present study, we analysed exons 2–4 of PADI4 in 102 German RA patients and 102 healthy individuals to study the influence of PADI4 variability on RA susceptibility by means of haplotype-specific DNA sequencing. Analyses of the influence of PADI4 and HLA-DRB1 genotypes on disease activity and on levels of anti-cyclic citrullinated peptide antibodies were performed.Comparing the frequencies of PADI4 haplotype 4 (padi4_89*G, padi4_90*T, padi4_92*G, padi4_94*T, padi4_104*C, padi4_95*G, padi4_96*T) (patients, 14.7%; controls, 7.8%; odds ratio = 2.0, 95% confidence interval = 1.1–3.8) and carriers of this haplotype (patients, 27.5%; controls, 13.7%; odds ratio = 2.4, 95% confidence interval = 1.2–4.8), a significant positive association of PADI4 haplotype 4 with RA could be demonstrated. Other PADI4 haplotypes did not differ significantly between patients and controls. Regarding the individual PADI4 variants, padi4_89 (A→G), padi4_90 (C→T), and padi4_94 (C→T) were significantly associated with RA (patients, 49.5%; controls, 38.7%; odds ratio = 1.6, 95% confidence interval = 1.1–2.3). Considering novel PADI4 variants located in or near to exons 2, 3, and 4, no quantitative or qualitative differences between RA patients (8.8%) and healthy controls (10.8%) could be demonstrated. While the PADI4 genotype did not influence disease activity and the anti-cyclic citrullinated peptide antibody level, the presence of the HLA-DRB1 shared epitope was significantly associated with higher anti-cyclic citrullinated peptide antibody levels (P = 0.033).The results of this small case–control study support the hypothesis that variability of the PADI4 gene may influence susceptibility to RA in the German population. Quantitative or qualitative differences in previously undefined PADI4 variants between patients and controls could not be demonstrated.
Highlights
Peptidylarginine deiminases (EC 3.5.3.15) are enzymes involved in the post-translational deimination of protein-bound arginine to citrulline [1]
Certain evidence suggests that deimination of arginine at those peptide side-chain positions that interact with the so-called shared epitope of some major hisanti-CCP = anti-cyclic citrullinated peptide antibodies; Peptidylarginine deiminase type 4 (PADI4) = peptidylarginine deiminase type 4; PCR = polymerase chain reaction; RA = rheumatoid arthritis; single nucleotide polymorphisms (SNPs) = single nucleotide polymorphism
A detailed description of the variability of exons 2–4 of the PADI4 gene in healthy individuals analysed by haplotype-specific DNA sequencing was given in our previous report [8]
Summary
Peptidylarginine deiminases (EC 3.5.3.15) are enzymes involved in the post-translational deimination of protein-bound arginine to citrulline [1]. Five different types of peptidylarginine deiminases encoded by the genes PADI1–PADI4 and PADI6 are currently known [1]. The presence of citrulline-modified target epitopes for autoantibodies is a well-known phenomenon in rheumatoid arthritis (RA) [2,3]. Peptidylarginine deiminases were recently implicated in the generation of anti-cyclic citrullinated peptide antibodies (anti-CCP) detectable in early stages of the disease [2,3,4]. Certain evidence suggests that deimination of arginine at those peptide side-chain positions that interact with the so-called shared epitope of some major hisanti-CCP = anti-cyclic citrullinated peptide antibodies; PADI4 = peptidylarginine deiminase type 4; PCR = polymerase chain reaction; RA = rheumatoid arthritis; SNP = single nucleotide polymorphism
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