Skip to main content

PADI4 polymorphisms and rheumatoid arthritis susceptibility: a meta-analysis

Rheumatology International volume 27, pages 827–833 (2007)Cite this article

Abstract

We conducted a comprehensive meta-analysis with all available data on the association of allele and genotype of peptidylarginine deiminases 4 (PADI4) polymorphisms with RA overall and in each ethnic population to explore whether the PADI4 polymorphisms confer susceptibility to RA. Nine comparisons, three Asians and six Europeans, from eight studies were included in this meta-analysis. Overall meta-analysis shows a significant association of PADI4_94, 104 and 90 with RA (OR = 1.20, 1.17, 1.35, P = 0.001, <0.0001, 0.006, respectively). There was a significant association with all of the PADI4 polymorphisms with RA in people of Asian descent. However, there was no significant association of PADI4 polymorphisms with RA in people of European descent, except for PADI_94. The presence of 2/2 genotype of the PADI4 significantly increased the risk for RA in European populations (OR = 2.10, 95% CI, 1.66–2.66, P < 0.0001) without between-study heterogeneity (I 2 = 44.3, P = 0.15). In conclusion, this meta-analysis demonstrates that the PADI4 polymorphisms may represent a significant risk factor for RA in Asians and Europeans and may play a larger role in susceptibility to RA in Asian than in European populations. Further studies are needed to see if the PADI4 gene confers a risk of RA in other ethnic groups.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Harris ED Jr (1990) Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 322:1277–1289

    PubMed  Article  Google Scholar 

  2. MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K et al (2000) Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 43:30–37

    PubMed  Article  CAS  Google Scholar 

  3. Wordsworth P, Bell J (1991) Polygenic susceptibility in rheumatoid arthritis. Ann Rheum Dis 50:343–346

    PubMed  CAS  Article  Google Scholar 

  4. Deighton CM, Walker DJ, Griffiths ID, Roberts DF (1989) The contribution of HLA to rheumatoid arthritis. Clin Genet 36:178–182

    PubMed  CAS  Article  Google Scholar 

  5. Schellekens GA, Visser H, de Jong BA, van den Hoogen FH, Hazes JM, Breedveld FC et al (2000) The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 43:155–163

    PubMed  Article  CAS  Google Scholar 

  6. Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ (2003) PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays 25:1106–1118

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  8. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M et al (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34:395–402

    PubMed  Article  CAS  Google Scholar 

  9. Cornelis F, Faure S, Martinez M, Prud’homme JF, Fritz P, Dib C et al (1998) New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study. Proc Natl Acad Sci USA 95:10746–10750

    PubMed  Article  CAS  Google Scholar 

  10. Shiozawa S, Hayashi S, Tsukamoto Y, Goko H, Kawasaki H, Wada T et al (1998) Identification of the gene loci that predispose to rheumatoid arthritis. Int Immunol 10:1891–1895

    PubMed  Article  CAS  Google Scholar 

  11. Ikari K, Kuwahara M, Nakamura T, Momohara S, Hara M, Yamanaka H et al (2005) Association between PADI4 and rheumatoid arthritis: a replication study. Arthritis Rheum 52:3054–3057

    PubMed  Article  CAS  Google Scholar 

  12. Kang CP, Lee HS, Ju H, Cho H, Kang C, Bae SC (2006) A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans. Arthritis Rheum 54:90–96

    PubMed  Article  CAS  Google Scholar 

  13. Barton A, Bowes J, Eyre S, Spreckley K, Hinks A, John S et al (2004) A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis Rheum 50:1117–1121

    PubMed  Article  CAS  Google Scholar 

  14. Martinez A, Valdivia A, Pascual-Salcedo D, Lamas JR, Fernandez-Arquero M, Balsa A et al (2005) PADI4 polymorphisms are not associated with rheumatoid arthritis in the Spanish population. Rheumatology (Oxford) 44:1263–1266

    Article  CAS  Google Scholar 

  15. Plenge RM, Padyukov L, Remmers EF, Purcell S, Lee AT, Karlson EW et al (2005) Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet 77:1044–1060

    PubMed  Article  CAS  Google Scholar 

  16. Caponi L, Petit-Teixeira E, Sebbag M, Bongiorni F, Moscato S, Pratesi F et al (2005) A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population. Ann Rheum Dis 64:587–593

    PubMed  Article  CAS  Google Scholar 

  17. Egger M, Smith GD, Phillips AN (1997) Meta-analysis: principles and procedures. BMJ 315:1533–1537

    PubMed  CAS  Google Scholar 

  18. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    PubMed  Article  Google Scholar 

  19. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    PubMed  Article  CAS  Google Scholar 

  20. Barton A, Bowes J, Eyre S, Symmons D, Worthington J, Silman A (2005) Investigation of polymorphisms in the PADI4 gene in determining severity of inflammatory polyarthritis. Ann Rheum Dis 64:1311–1315

    PubMed  Article  CAS  Google Scholar 

  21. Harney SM, Meisel C, Sims AM, Woon PY, Wordsworth BP, Brown MA (2005) Genetic and genomic studies of PADI4 in rheumatoid arthritis. Rheumatology (Oxford) 44:869–872

    Article  CAS  Google Scholar 

  22. Hoppe B, Haupl T, Gruber R, Kiesewetter H, Burmester GR, Salama A et al (2006) Detailed analysis of the variability of peptidylarginine deiminase type 4 in German patients with rheumatoid arthritis: a case-control study. Arthritis Res Ther 8:R34

    PubMed  Article  CAS  Google Scholar 

  23. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309

    PubMed  Article  CAS  Google Scholar 

  24. Iwamoto T, Ikari K, Nakamura T, Kuwahara M, Toyama Y, Tomatsu T et al (2006) Association between PADI4 and rheumatoid arthritis: a meta-analysis. Rheumatology 45:804–807

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, 126-1 Ka, Anam-Dong, Seongbuk-Ku, Seoul, 136-705, Korea

    Young Ho Lee, Young Hee Rho, Seong Jae Choi, Jong Dae Ji & Gwan Gyu Song

Authors
  1. Young Ho Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Young Hee Rho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seong Jae Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jong Dae Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gwan Gyu Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Young Ho Lee.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lee, Y.H., Rho, Y.H., Choi, S.J. et al. PADI4 polymorphisms and rheumatoid arthritis susceptibility: a meta-analysis. Rheumatol Int 27, 827–833 (2007). https://doi.org/10.1007/s00296-007-0320-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-007-0320-y

Keywords

  • Rheumatoid arthritis
  • PADI4
  • Polymorphism
  • Meta-analysis