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Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis.

ABSTRACT: Protein citrullination is an important posttranslational modification recognized by rheumatoid arthritis (RA)-specific autoantibodies. One of the citrullinating enzymes, peptidyl arginine deiminase type 4 (PAD-4), is genetically associated with development of RA in some populations, although the mechanism(s) mediating this effect are not yet clear. There have been descriptions of anti-PAD-4 autoantibodies in different rheumatic diseases. This study was undertaken to investigate whether anti-PAD-4 antibodies are specific to RA, are associated with disease phenotype or severity, and whether PAD-4 polymorphisms influence the anti-PAD-4 autoantibody response.Sera from patients with established RA, patients with other rheumatic diseases, and healthy adults were assayed for anti-PAD-4 autoantibodies by immunoprecipitation of in vitro-translated PAD-4. The epitope(s) recognized by PAD-4 autoantibodies were mapped using various PAD-4 truncations. PAD-4 genotyping was performed on RA patients with the TaqMan assay. Joint erosions were scored from hand and foot radiographs using the Sharp/van der Heijde method.PAD-4 autoantibodies were found in 36-42% of RA patients, and were very infrequent in controls. Recognition by anti-PAD-4 autoantibodies required the 119 N-terminal amino acids, which encompass the 3 nonsynonymous polymorphisms associated with disease susceptibility. Strikingly, the anti-PAD-4 immune response was associated with the RA susceptibility haplotype of PADI4. Anti-PAD-4 antibodies were associated with more severe joint destruction in RA.Our findings indicate that anti-PAD-4 antibodies are specific markers of RA, independently associated with more severe disease, suggesting that an anti-PAD-4 immune response may be involved in pathways of joint damage in this disease. Polymorphisms in the PADI4 gene influence the immune response to the PAD-4 protein, potentially contributing to disease propagation.

SUBMITTER: Harris ML

PROVIDER: S-EPMC2692635 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis.

Harris Michelle L ML Darrah Erika E Lam Gordon K GK Bartlett Susan J SJ Giles Jon T JT Grant Audrey V AV Gao Peisong P Scott William W WW El-Gabalawy Hani H Casciola-Rosen Livia L Barnes Kathleen C KC Bathon Joan M JM Rosen Antony A

Arthritis and rheumatism 20080701 7

<h4>Objective</h4>Protein citrullination is an important posttranslational modification recognized by rheumatoid arthritis (RA)-specific autoantibodies. One of the citrullinating enzymes, peptidyl arginine deiminase type 4 (PAD-4), is genetically associated with development of RA in some populations, although the mechanism(s) mediating this effect are not yet clear. There have been descriptions of anti-PAD-4 autoantibodies in different rheumatic diseases. This study was undertaken to investigate ...[more]

PMID: 18576335

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Project description:IntroductionAnti-cyclic citrullinated peptide autoantibodies (anti-CCP) are the most specific serologic marker for rheumatoid arthritis (RA). Genetic polymorphisms in a citrullinating (or deiminating) enzyme, peptidyl arginine deiminase type IV (PADI4) have been reproducibly associated with RA susceptibility in several populations. We investigated whether PADI4 polymorphisms contribute to anti-CCP-negative as well as -positive RA, whether they influence disease severity (erosive joint status), and whether they interact with two major risk factors for RA, Human Leukocyte Antigen-DRB1 (HLA-DRB1) shared epitope (SE) alleles and smoking, depending on anti-CCP and erosive joint status.MethodsAll 2,317 unrelated Korean subjects including 1,313 patients with RA and 1,004 unaffected controls were genotyped for three nonsynonymous (padi4_89, padi4_90, and padi4_92) and one synonymous (padi4_104) single-nucleotide polymorphisms (SNPs) in PADI4 and for HLA-DRB1 by direct DNA sequence analysis. Odds ratios (OR) were calculated by multivariate logistic regression. Interaction was evaluated by attributable proportions (AP), with 95% confidence intervals (CI).ResultsA functional haplotype of the three fully correlated nonsynonymous SNPs in PADI4 was significantly associated with susceptibility to not only anti-CCP-positive (adjusted OR 1.73, 95% CI 1.34 to 2.23) but also -negative RA (adjusted OR 1.75, 95% CI 1.15 to 2.68). A strong association with both non-erosive (adjusted OR 1.62, 95% CI 1.29 to 2.05) and erosive RA (adjusted OR 1.62, 95% CI 1.14 to 2.31) was observed for PADI4 haplotype. Gene-gene interactions between the homozygous RA-risk PADI4 haplotype and SE alleles were significant in both anti-CCP-positive (AP 0.45, 95% CI 0.20 to 0.71) and -negative RA (AP 0.61, 95% CI 0.29 to 0.92). Theses interactions were also observed for both non-erosive (AP 0.48, 95% CI 0.25 to 0.72) and erosive RA (AP 0.46, 95% CI 0.14 to 0.78). In contrast, no interaction was observed between smoking and PADI4 polymorphisms.ConclusionsA haplotype of nonsynonymous SNPs in PADI4 contributes to development of RA regardless of anti-CCP or erosive joint status. The homozygous PADI4 haplotype contribution is affected by gene-gene interactions with HLA-DRB1 SE alleles.

Dataset Information

Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis.

Publications

Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis.

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