Skip to main content

Advertisement

Springer Nature Link
Log in

Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis

  • Article
  • Published:

From Nature Genetics

View current issue Submit your manuscript

Abstract

Individuals with rheumatoid arthritis frequently have autoantibodies to citrullinated peptides, suggesting the involvement of the peptidylarginine deiminases citrullinating enzymes (encoded by PADI genes) in rheumatoid arthritis. Previous linkage studies have shown that a susceptibility locus for rheumatoid arthritis includes four PADI genes but did not establish which PADI gene confers susceptibility to rheumatoid arthritis. We used a case-control linkage disequilibrium study to show that PADI type 4 is a susceptibility locus for rheumatoid arthritis (P = 0.000008). PADI4 was expressed in hematological and rheumatoid arthritis synovial tissues. We also identified a haplotype of PADI4 associated with susceptibility to rheumatoid arthritis that affected stability of transcripts and was associated with levels of antibody to citrullinated peptide in sera from individuals with rheumatoid arthritis. Our results imply that the PADI4 haplotype associated with susceptibility to rheumatoid arthritis increases production of citrullinated peptides acting as autoantigens, resulting in heightened risk of developing the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1: Gene content of NT_034367.1 in chromosome 1p36, case-control association and linkage disequilibrium.
Figure 2: Structure of PADI4.
Figure 3: Expression of PADI4.
Figure 4: Stability of susceptible and non-susceptible transcripts of PADI4 mRNA measured as degradation rate.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Seldin, M.F., Amos, C.I., Ward, R. & Gregersen, P.K. The genetics revolution and the assault on rheumatoid arthritis. Arthritis Rheum. 42, 1071–1079 (1999).

    Article  CAS  Google Scholar 

  2. Gregersen, P.K., Silver, J. & Winchester, R.J. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987).

    Article  CAS  Google Scholar 

  3. Nepom, G.T. Major histocompatibility complex–directed susceptibility to rheumatoid arthritis. Adv. Immunol. 68, 315–332 (1998).

    Article  CAS  Google Scholar 

  4. Weyand, C.M. & Goronzy, J.J. Association of MHC and rheumatoid arthritis. HLA polymorphisms in phenotypic variants of rheumatoid arthritis. Arthritis Res. 2, 212–216 (2000).

    Article  CAS  Google Scholar 

  5. Cornelis, F. et al. New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study. Proc. Natl. Acad. Sci. USA 95, 10746–10750 (1998).

    Article  CAS  Google Scholar 

  6. Jawaheer, D. et al. A genome-wide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. Am. J. Hum. Genet. 68, 927–936 (2001).

    Article  CAS  Google Scholar 

  7. MacKay, K. et al. Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom. Arthritis Rheum. 46, 632–639 (2002).

    Article  CAS  Google Scholar 

  8. Shiozawa, S. et al. Identification of the gene loci that predispose to rheumatoid arthritis. Int. Immunol. 10, 1891–1895 (1998).

    Article  CAS  Google Scholar 

  9. Schellekens, G.A., de Jong, B.A., van den Hoogen, F.H., van de Putte, L.B. & van Venrooij, W.J. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J. Clin. Invest. 101, 273–281 (1998).

    Article  CAS  Google Scholar 

  10. Menard, H.A., Lapointe, E., Rochdi, M.D. & Zhou, Z.J. Insights into rheumatoid arthritis derived from the Sa immune system. Arthritis Res. 2, 429–432 (2000).

    Article  CAS  Google Scholar 

  11. Schellekens, G.A. et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 43, 155–163 (2000).

    Article  CAS  Google Scholar 

  12. Nogueira, L. et al. Performance of two ELISAs for antifilaggrin autoantibodies, using either affinity purified or deiminated recombinant human filaggrin, in the diagnosis of rheumatoid arthritis. Ann. Rheum. Dis. 60, 882–887 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Goldbach-Mansky, R. et al. Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset. Arthritis Res. 2, 236–243 (2000).

    Article  CAS  Google Scholar 

  14. Masson-Bessiere, C. et al. The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the α- and β-chains of fibrin. J. Immunol. 166, 4177–4184 (2001).

    Article  CAS  Google Scholar 

  15. Baeten, D. et al. Specific presence of intracellular citrullinated proteins in rheumatoid arthritis synovium: relevance to antifilaggrin autoantibodies. Arthritis Rheum. 44, 2255–2262 (2001).

    Article  CAS  Google Scholar 

  16. Zhou, Z. & Menard, H.A. Autoantigenic posttranslational modifications of proteins: does it apply to rheumatoid arthritis? Curr. Opin. Rheumatol. 14, 250–253 (2002).

    Article  CAS  Google Scholar 

  17. Ozaki, K. et al. Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction. Nat. Genet. 32, 650–654 (2002).

    Article  CAS  Google Scholar 

  18. Ohnishi, Y. et al. A high-throughput SNP typing system for genome-wide association studies. J. Hum. Genet. 46, 471–477 (2001).

    Article  CAS  Google Scholar 

  19. McIntyre, L.M., Martin, E.R., Simonsen, K.L. & Kaplan, N.L. Circumventing multiple testing: a multilocus Monte Carlo approach to testing for association. Genet. Epidemiol. 19, 18–29 (2000).

    Article  CAS  Google Scholar 

  20. Nakashima, K. et al. Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1alpha,25-dihydroxyvitamin D(3). J. Biol. Chem. 274, 27786–27792 (1999).

    Article  CAS  Google Scholar 

  21. Cuadrado, A. et al. HuD binds to three AU-rich sequences in the 3′ UTR of neuroserpin mRNA and promotes the accumulation of neuroserpin mRNA and protein. Nucleic Acids Res. 30, 2202–2211 (2002).

    Article  CAS  Google Scholar 

  22. Vincent, C. et al. Detection of antibodies to deiminated recombinant rat filaggrin by enzyme-linked immunosorbent assay: a highly effective test for the diagnosis of rheumatoid arthritis. Arthritis Rheum. 46, 2051–2058 (2002).

    Article  CAS  Google Scholar 

  23. van Venrooij, W.J. & Pruijn, G.J. Citrullination: a small change for a protein with great consequences for rheumatoid arthritis. Arthritis Res. 2, 249–251 (2000).

    Article  CAS  Google Scholar 

  24. Vincent, C. et al. High diagnostic value in rheumatoid arthritis of antibodies to the stratum corneum of rat oesophagus epithelium, so-called 'antikeratin antibodies'. Ann. Rheum. Dis. 48, 712–722 (1989).

    Article  CAS  Google Scholar 

  25. Gomes-Daudrix, V. et al. Immunoblotting detection of so-called 'antikeratin antibodies': a new assay for the diagnosis of rheumatoid arthritis. Ann. Rheum. Dis. 53, 735–742 (1994).

    Article  CAS  Google Scholar 

  26. Vincent, C. et al. Immunoblotting detection of autoantibodies to human epidermis filaggrin: a new diagnostic test for rheumatoid arthritis. J. Rheumatol. 25, 838–846 (1998).

    CAS  PubMed  Google Scholar 

  27. Shibue, T. et al. Tumor necrosis factor α 5′-flanking region, tumor necrosis factor receptor II, and HLA-DRB1 polymorphisms in Japanese patients with rheumatoid arthritis. Arthritis Rheum. 43, 753–757 (2000).

    Article  CAS  Google Scholar 

  28. de Vries, N., Tijssen, H., van Riel, P.L. & van de Putte, L.B. Reshaping the shared epitope hypothesis: HLA-associated risk for rheumatoid arthritis is encoded by amino acid substitutions at positions 67-74 of the HLA-DRB1 molecule. Arthritis Rheum. 46, 921–928 (2002).

    Article  CAS  Google Scholar 

  29. Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).

    Article  CAS  Google Scholar 

  30. Schildkraut, J.M. Examining complex genetic interactions. in Approach to Gene Mapping in Complex Human Diseases (eds. J.L. Haines and M.A. Pericak-Vance) 379–410 (Wiley-Liss, New York, 1998).

    Google Scholar 

  31. Asaga, H., Nakashima, K., Senshu, T., Ishigami, A. & Yamada, M. Immunocytochemical localization of peptidylarginine deiminase in human eosinophils and neutrophils. J. Leukoc. Biol. 70, 46–51 (2001).

    CAS  PubMed  Google Scholar 

  32. Pillinger, M.H. & Abramson, S.B. The neutrophil in rheumatoid arthritis. Rheum. Dis. Clin. North Am. 21, 691–714 (1995).

    CAS  PubMed  Google Scholar 

  33. Hirano, T. Revival of the autoantibody model in rheumatoid arthritis. Nat. Immunol. 3, 342–344 (2002).

    Article  CAS  Google Scholar 

  34. Zhou, X. et al. Association of novel polymorphisms with the expression of SPARC in normal fibroblasts and with susceptibility to scleroderma. Arthritis Rheum. 46, 2990–2999 (2002).

    Article  CAS  Google Scholar 

  35. Yang, T., McNally, B.A., Ferrone, S., Liu, Y. & Zheng, P. A single nucleotide deletion leads to rapid degradation of TAP-1 mRNA in a melanoma cell line. J. Biol. Chem. 278, 15291–15296 (2003).

    Article  CAS  Google Scholar 

  36. Jansen, A.L. et al. Rheumatoid factor and antibodies to cyclic citrullinated Peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis. J. Rheumatol. 29, 2074–2076 (2002).

    PubMed  Google Scholar 

  37. Arnett, F.C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988).

    Article  CAS  Google Scholar 

  38. Hirakawa, M. et al. JSNP: a database of common gene variations in the Japanese population. Nucleic Acids Res. 30, 158–162 (2002).

    Article  CAS  Google Scholar 

  39. Ott, J. Counting methods (EM algorithm) in human pedigree analysis: linkage and segregation analysis. Ann. Hum. Genet. 40, 443–454 (1977).

    Article  CAS  Google Scholar 

  40. Devlin, B. & Risch, N. A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 29, 311–322 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank E. Tatsu, K. Kobayashi, M. Mito, N. Iwamoto and the other members of the rheumatoid arthritis team for their advice and technical assistance; H. Kawakami for his expertise in computer programming; and many members of the SNP Research Center for helpful discussions and assistance with various aspects of this study. This work was supported by a grant from the Japanese Millennium Project.

Author information

Authors and Affiliations

  1. Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 1-7-22, Suehirocho, Tsurumi-ku, Yokohama City, 230-0045, Kanagawa, Japan

    Akari Suzuki, Ryo Yamada, Xiaotian Chang, Shinya Tokuhiro & Kazuhiko Yamamoto

  2. Sankyo, Tokyo, Japan

    Shinya Tokuhiro, Masakatsu Suzuki, Miyuki Nagasaki, Makiko Nakayama-Hamada, Reimi Kawaida, Mitsuru Ono, Masahiko Ohtsuki & Hidehiko Furukawa

  3. Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan

    Tetsuji Sawada & Kazuhiko Yamamoto

  4. Department of Joint Disease and Rheumatism, Nippon Medical School, Tokyo, Japan

    Shinichi Yoshino

  5. Yukioka Hospital, Osaka, Japan

    Masao Yukioka

  6. National Sagamihara Hospital, Kanagawa, Japan

    Shigeto Tohma

  7. Matsubara Mayflower Hospital, Hyogo, Japan

    Tsukasa Matsubara

  8. Osaka Minami National Hospital, Osaka, Japan

    Shigeyuki Wakitani

  9. Department of Orthopedic Surgery, Tottori University, Tottori, Japan

    Ryota Teshima

  10. Yamanashi Prefectural Central Hospital, Yamanashi, Japan

    Yuichi Nishioka

  11. Laboratory for Genotyping, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan

    Akihiro Sekine, Aritoshi Iida & Yusuke Nakamura

  12. Laboratory for Medical Informatics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan

    Atsushi Takahashi & Tatsuhiko Tsunoda

  13. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Yusuke Nakamura

Authors
  1. Akari Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryo Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaotian Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shinya Tokuhiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tetsuji Sawada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masakatsu Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Miyuki Nagasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Makiko Nakayama-Hamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Reimi Kawaida
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mitsuru Ono
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masahiko Ohtsuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hidehiko Furukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shinichi Yoshino
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Masao Yukioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Shigeto Tohma
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Tsukasa Matsubara
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Shigeyuki Wakitani
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Ryota Teshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Yuichi Nishioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Akihiro Sekine
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Aritoshi Iida
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Atsushi Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Tatsuhiko Tsunoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Yusuke Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Kazuhiko Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ryo Yamada.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Suzuki, A., Yamada, R., Chang, X. et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34, 395–402 (2003). https://doi.org/10.1038/ng1206

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1206

  • Springer Nature America, Inc.

This article is cited by

Search

Navigation