Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans

Abstract

Increased expression of interferon (IFN)-inducible genes is implicated in the pathogenesis of systemic lupus erythematosus (SLE). One transcription factor responsible for regulating IFN, interferon regulatory factor-5 (IRF5), has been associated with SLE in genetic studies of Asian, Caucasian and Hispanic populations. We genotyped up to seven polymorphic loci in or near IRF5 in a total of 4870 African-American and Caucasian subjects (1829 SLE sporadic cases and 3041 controls) from two independent studies. Population-based case–control comparisons were performed using the Pearson's χ2-test statistics and haplotypes were inferred using HaploView. We observed significant novel associations with the IRF5 variants rs2004640 and rs3807306 in African Americans and replicated previously reported associations in Caucasians. While we identified risk haplotypes, the majority of haplotypic effects were accounted for by one SNP (rs3807306) in conditional analyses. We conclude that genetic variants of IRF5 associate with SLE in multiple populations, providing evidence that IRF5 is likely to be a crucial component in SLE pathogenesis among multiple ethnic groups.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Hochberg MC . The epidemiology of systemic lupus erythematosus. In: Wallace DJ, Hahn BH (eds). Dubois' Lupus Erythematosus. Williams and Wilkins: Baltimore, 1997, pp 49–65.

    Google Scholar 

  2. Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998; 41: 778–799.

    Article  CAS  Google Scholar 

  3. Alarcon GS, Friedman AW, Straaton KV, Moulds JM, Lisse J, Bastian HM et al. Systemic lupus erythematosus in three ethnic groups: III. A comparison of characteristics early in the natural history of the LUMINA cohort. LUpus in MInority populations: NAture vs. Nurture. Lupus 1999; 8: 197–209.

    Article  CAS  Google Scholar 

  4. Hochberg MC . Updating the American college of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.

    Article  CAS  Google Scholar 

  5. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–1277.

    Article  CAS  Google Scholar 

  6. Harley JB, Kelly JA, Kaufman KM . Unraveling the genetics of systemic lupus erythematosus. Springer Semin Immunopathol 2006; 28: 119–130.

    Article  CAS  Google Scholar 

  7. Sarzi-Puttini P, Atzeni F, Iaccarino L, Doria A . Environment and systemic lupus erythematosus: an overview. Autoimmunity 2005; 38: 465–472.

    Article  CAS  Google Scholar 

  8. James JA, Harley JB, Scofield RH . Role of viruses in systemic lupus erythematosus and Sjogren syndrome. Curr Opin Rheumatol 2001; 13: 370–376.

    Article  CAS  Google Scholar 

  9. Baechler EC, Gregersen PK, Behrens TW . The emerging role of interferon in human systemic lupus erythematosus. Curr Opin Immunol 2004; 16: 801–807.

    Article  CAS  Google Scholar 

  10. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N . IRF family of transcription factors as regulators of host defense. Annu Rev Immunol 2001; 19: 623–655.

    Article  CAS  Google Scholar 

  11. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 2005; 434: 243–249.

    Article  CAS  Google Scholar 

  12. Graham RR, Kozyrev SV, Baechler EC, Reddy MV, Plenge RM, Bauer JW et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet 2006; 38: 550–555.

    Article  CAS  Google Scholar 

  13. Graham RR, Kyogoku C, Sigurdsson S, Vlasova IA, Davies LR, Baechler EC et al. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc Natl Acad Sci USA 2007; 104: 6758–6763.

    Article  CAS  Google Scholar 

  14. Kozyrev SV, Lewen S, Reddy PM, Pons-Estel B, Witte T, Junker P et al. Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus. Arthritis Rheum 2007; 56: 1234–1241.

    Article  CAS  Google Scholar 

  15. Reddy MV, Velazquez-Cruz R, Baca V, Lima G, Granados J, Orozco L et al. Genetic association of IRF5 with SLE in Mexicans: higher frequency of the risk haplotype and its homozygozity than Europeans. Hum Genet 2007; 121: 721–727.

    Article  Google Scholar 

  16. Shin HD, Sung YK, Choi CB, Lee SO, Lee HW, Bae SC . Replication of the genetic effects of IFN regulatory factor 5 (IRF5) on systemic lupus erythematosus in a Korean population. Arthritis Res Ther 2007; 9: R32.

    Article  Google Scholar 

  17. Cunninghame Graham DS, Manku H, Wagner S, Reid J, Timms K, Gutin A et al. Association of IRF5 in UK SLE families identifies a variant involved in polyadenylation. Hum Mol Genet 2007; 16: 579–591.

    Article  CAS  Google Scholar 

  18. Sigurdsson S, Nordmark G, Goring HH, Lindroos K, Wiman AC, Sturfelt G et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 2005; 76: 528–537.

    Article  CAS  Google Scholar 

  19. Demirci FY, Manzi S, Ramsey-Goldman R, Minster RL, Kenney M, Shaw PS et al. Association of a common interferon regulatory factor 5 (IRF5) variant with increased risk of systemic lupus erythematosus (SLE). Ann Hum Genet 2007; 71 (Part 3): 308–311.

    Article  CAS  Google Scholar 

  20. Sigurdsson S, Goring HH, Kristjansdottir G, Milani L, Nordmark G, Sandling J et al. Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 reveals a novel 5bp length polymorphism as strong risk factor for systemic lupus erythematosus. Hum Mol Genet 2007 (doi:10.1093/hmg/ddm359).

    Article  Google Scholar 

  21. Ferreiro-Neira I, Calaza M, Alonso-Perez E, Marchini M, Scorza R, Sebastiani GD et al. Opposed independent effects and epistasis in the complex association of IRF5 to SLE. Genes Immun 2007; 8: 429–438.

    Article  CAS  Google Scholar 

  22. Ioannidis JP, Ntzani EE, Trikalinos TA . ‘Racial’ differences in genetic effects for complex diseases. Nat Genet 2004; 36: 1312–1318.

    Article  CAS  Google Scholar 

  23. Conrad DF, Jakobsson M, Coop G, Wen X, Wall JD, Rosenberg NA et al. A worldwide survey of haplotype variation and linkage disequilibrium in the human genome. Nat Genet 2006; 38: 1251–1260.

    Article  CAS  Google Scholar 

  24. Ioannidis JP, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG . Genetic associations in large versus small studies: an empirical assessment. Lancet 2003; 361: 567–571.

    Article  Google Scholar 

  25. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG . The functional p53 codon 72 polymorphism is associated with systemic lupus erythematosus. Lupus 2005; 14: 842–845.

    Article  CAS  Google Scholar 

  26. Sanchez E, Sabio JM, Callejas JL, de Ramon E, de Haro M, Jimenez-Alonso J et al. Study of a functional polymorphism in the p53 gene in systemic lupus erythematosus: lack of replication in a Spanish population. Lupus 2006; 15: 658–661.

    Article  CAS  Google Scholar 

  27. Vargas-Alarcon G, Granados J, Martinez-Laso J, Gomez-Casado E, Zuniga J, Salgado N et al. Lack of association between the polymorphism at the heat-shock protein (HSP70-2) gene and systemic lupus erythematosus (SLE) in the Mexican mestizo population. Genes Immun 2000; 1: 367–370.

    Article  CAS  Google Scholar 

  28. Lee YH, Harley JB, Nath SK . CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis. Hum Genet 2005; 116: 361–367.

    Article  CAS  Google Scholar 

  29. Szalai AJ, Alarcon GS, Calvo-Alen J, Toloza SM, McCrory MA, Edberg JC et al. Systemic lupus erythematosus in a multiethnic US Cohort (LUMINA). XXX: association between C-reactive protein (CRP) gene polymorphisms and vascular events. Rheumatology (Oxford) 2005; 44: 864–868.

    Article  CAS  Google Scholar 

  30. Thorburn CM, Prokunina-Olsson L, Sterba KA, Lum RF, Seldin MF, Alarcon-Riquelme ME et al. Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort. Genes Immun 2007; 8: 279–287.

    Article  CAS  Google Scholar 

  31. Parks CG, Pandey JP, Dooley MA, Treadwell EL, St Clair EW, Gilkeson GS et al. Genetic polymorphisms in tumor necrosis factor (TNF)-alpha and TNF-beta in a population-based study of systemic lupus erythematosus: associations and interaction with the interleukin-1alpha-889 C/T polymorphism. Hum Immunol 2004; 65: 622–631.

    Article  CAS  Google Scholar 

  32. Kaufman KM, Kelly JA, Herring BJ, Adler AJ, Glenn SB, Namjou B et al. Evaluation of the genetic association of the PTPN22 R620W polymorphism in familial and sporadic systemic lupus erythematosus. Arthritis Rheum 2006; 54: 2533–2540.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Debbie McDuffie, Lifeng Zhang and Julius Tate (UAB) for technical assistance. We also acknowledge our study participants without whom this study would not have been possible. This work was supported by the NIH (AI24717, AI31584, AI53747, AI62629, AR12253, AR33062, AR42460, AR42476, AR43727, DE15223, P01-AR49084, K24-AR02138, MO1-RR00032, MO1-RR00048, M01-RR00052, P60-AR48098, RR15577, RR20143 and T32-AR07450), the Alliance for Lupus Research, the American College of Rheumatology Research and Education Foundation, Mary Kirland Scholar, Program for Research Experience in Pathology (UAB), University of Alabama Health Sciences Foundation, and the US Department of Veterans Affairs.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to J B Harley or J C Edberg.

Additional information

Disclosure

The authors declare no conflict of interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kelly, J., Kelley, J., Kaufman, K. et al. Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans. Genes Immun 9, 187–194 (2008). https://doi.org/10.1038/gene.2008.4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2008.4

Keywords

This article is cited by

Search

Quick links