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.

Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways

Abstract

Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 × 10−8). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-α and regulate NF-κB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Bird's eye view of association scan results.
Figure 2: Evidence for association in confirmed loci.

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Lowes, M.A., Bowcock, A.M. & Krueger, J.G. Pathogenesis and therapy of psoriasis. Nature 445, 866–873 (2007).

    Article  CAS  Google Scholar 

  2. Nair, R.P. et al. Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am. J. Hum. Genet. 78, 827–851 (2006).

    Article  CAS  Google Scholar 

  3. Cargill, M. et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).

    Article  CAS  Google Scholar 

  4. Yates, V.M., Watkinson, G. & Kelman, A. Further evidence for an association between psoriasis, Crohn's disease and ulcerative colitis. Br. J. Dermatol. 106, 323–330 (1982).

    Article  CAS  Google Scholar 

  5. Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Genet. 39, 830–832 (2007).

    Article  CAS  Google Scholar 

  6. Manolio, T.A. et al. New models of collaboration in genome-wide association studies: the Genetic Association Information Network. Nat. Genet. 39, 1045–1051 (2007).

    Article  CAS  Google Scholar 

  7. Bettelli, E., Oukka, M. & Kuchroo, V.K. TH-17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8, 345–350 (2007).

    Article  CAS  Google Scholar 

  8. Lee, E.G. et al. Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 289, 2350–2354 (2000).

    Article  CAS  Google Scholar 

  9. Chan, J.R. et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J. Exp. Med. 203, 2577–2587 (2006).

    Article  CAS  Google Scholar 

  10. Wang, H. et al. A 9-centimorgan interval of chromosome 10 controls the T cell-dependent psoriasiform skin disease and arthritis in a murine psoriasis model. J. Immunol. 180, 5520–5529 (2008).

    Article  CAS  Google Scholar 

  11. Idel, S., Dansky, H.M. & Breslow, J.L. A20, a regulator of NFkappaB, maps to an atherosclerosis locus and differs between parental sensitive C57BL/6J and resistant FVB/N strains. Proc. Natl. Acad. Sci. USA 100, 14235–14240 (2003).

    Article  CAS  Google Scholar 

  12. Gelfand, J.M. et al. Risk of myocardial infarction in patients with psoriasis. J. Am. Med. Assoc. 296, 1735–1741 (2006).

    Article  CAS  Google Scholar 

  13. Krueger, G.G. et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N. Engl. J. Med. 356, 580–592 (2007).

    Article  CAS  Google Scholar 

  14. Chaudhari, U. et al. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 357, 1842–1847 (2001).

    Article  CAS  Google Scholar 

  15. Plenge, R.M. et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat. Genet. 39, 1477–1482 (2007).

    Article  CAS  Google Scholar 

  16. Graham, R.R. et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat. Genet. 40, 1059–1061 (2008).

    Article  CAS  Google Scholar 

  17. Musone, S.L. et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat. Genet. 40, 1062–1064 (2008).

    Article  CAS  Google Scholar 

  18. Kryczek, I. et al. Induction of memory IL-17+ T cell trafficking and expansion by IFN-gamma: Mechanism and pathological relevance. J. Immunol. 181, 4733–4741 (2008).

    Article  CAS  Google Scholar 

  19. Chang, M. et al. Variants in the 5q31 cytokine gene cluster are associated with psoriasis. Genes Immun. 9, 176–181 (2008).

    Article  CAS  Google Scholar 

  20. Lettre, G. et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nat. Genet. 40, 584–591 (2008).

    Article  CAS  Google Scholar 

  21. Chandran, V. et al. Familial aggregation of psoriatic arthritis. Ann. Rheum. Dis. advance online publication, doi:10.1136/ard.2008.089367 (4 June 2008).

  22. Zhou, X. et al. Novel mechanisms of T-cell and dendritic cell activation revealed by profiling of psoriasis on the 63,100-element oligonucleotide array. Physiol. Genomics 13, 69–78 (2003).

    Article  CAS  Google Scholar 

  23. Elder, J.T. et al. The genetics of psoriasis. Arch. Dermatol. 130, 216–224 (1994).

    Article  CAS  Google Scholar 

  24. Hollox, E.J. et al. Psoriasis is associated with increased beta-defensin genomic copy number. Nat. Genet. 40, 23–25 (2008).

    Article  CAS  Google Scholar 

  25. de Cid, R. et al. Deletion of the late cornified envelope LCE3C and LCE3B genes as a susceptibility factor for psoriasis. Nat. Genet. advance online publication, doi: 10.1038/ng.313 (25 January 2009).

  26. Capon, F. et al. Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene. Hum. Mol. Genet. 17, 1938–1945 (2008).

    Article  CAS  Google Scholar 

  27. Liu, Y. et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease Loci. PLoS Genet. 4, e1000041 (2008).

    Article  Google Scholar 

  28. Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).

    Article  CAS  Google Scholar 

  29. Frazer, K.A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

    Article  CAS  Google Scholar 

  30. Thornton, T. & McPeek, M.S. Case-control association testing with related individuals: a more powerful quasi-likelihood score test. Am. J. Hum. Genet. 81, 321–337 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge funding from the National Institutes of Health, the Foundation for NIH's Genetic Association Information Network and the National Psoriasis Foundation. Analysis and genotyping of follow-up samples was also supported by the German National Genome Research Network (BMFT 01GS 0171/BMBF NUW-S23T10) and POPGEN Biobank (BMBF 01GR0468), by the Canadian Institute of Health Research and the Arthritis Society of Canada, by the Centre National de Génotypage, Généthon and the Association Française contre les Myopathies (AFM), and by Celera Corporation.

Author information

Authors and Affiliations

Authors

Consortia

Contributions

J.T.E., G.G.K., A.M.B. and G.R.A. designed and directed the study. J.D., C.H., P.E.S., D. Goldgar, B.J.F., Y.L. and G.R.A. designed and carried out the main genome scan analysis. R.P.N., K.C.D., C.H., J.D., P.E.S., J.E.G., T.T., S.P., S.L.G., W.L., P.-Y.K., A.M., C.A.W., J.J.V., J.T.E, G.G.K. and A.M.B. provided samples for the initial genome-wide association scan and replication and executed the experiments. A.R., S.S., M.W., D. Gladman, P.R., S.J.S., J.F., G.M.L. and A.B.B. provided additional replication data. J.D., J.T.E. and G.R.A. generated the first draft of the paper. Additional major edits were done by K.C.D., P.E.S., A.B.B., G.G.K. and A.M.B. All authors reviewed and approved the paper.

Corresponding authors

Correspondence to James T Elder, Gerald G Krueger, Anne M Bowcock or Gonçalo R Abecasis.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–7 and Supplementary Figure 1 (PDF 192 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nair, R., Duffin, K., Helms, C. et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat Genet 41, 199–204 (2009). https://doi.org/10.1038/ng.311

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.311

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing