Letter | Published:

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

Nature Genetics 41, 199–204 (2009) | Download Citation

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

Accessions

Gene Expression Omnibus

References

  1. 1.

    , & Pathogenesis and therapy of psoriasis. Nature 445, 866–873 (2007).

  2. 2.

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

  3. 3.

    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).

  4. 4.

    , & Further evidence for an association between psoriasis, Crohn's disease and ulcerative colitis. Br. J. Dermatol. 106, 323–330 (1982).

  5. 5.

    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).

  6. 6.

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

  7. 7.

    , & TH-17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8, 345–350 (2007).

  8. 8.

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

  9. 9.

    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).

  10. 10.

    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).

  11. 11.

    , & 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).

  12. 12.

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

  13. 13.

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

  14. 14.

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

  15. 15.

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

  16. 16.

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

  17. 17.

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

  18. 18.

    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).

  19. 19.

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

  20. 20.

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

  21. 21.

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

  22. 22.

    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).

  23. 23.

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

  24. 24.

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

  25. 25.

    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. 26.

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

  27. 27.

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

  28. 28.

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

  29. 29.

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

  30. 30.

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

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

    • Rajan P Nair
    • , Kristina Callis Duffin
    • , Cynthia Helms
    •  & Jun Ding

    These authors contributed equally to this work.

    • James T Elder
    • , Gerald G Krueger
    • , Anne M Bowcock
    •  & Gonçalo R Abecasis

    These authors contributed equally to this work.

Affiliations

  1. Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Rajan P Nair
    • , Philip E Stuart
    • , Johann E Gudjonsson
    • , Trilokraj Tejasvi
    • , John J Voorhees
    • , James T Elder
    •  & Ravi Hiremagalore

  2. Department of Dermatology, University of Utah, Salt Lake City, Utah 84131, USA.

    • Kristina Callis Duffin
    • , David Goldgar
    • , Bing-Jian Feng
    •  & Gerald G Krueger

  3. Division of Human Genetics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

    • Cynthia Helms
    • , Anne M Bowcock
    •  & Jennifer Gardner

  4. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Jun Ding
    • , Yun Li
    •  & Gonçalo R Abecasis

  5. Institute for Clinical Molecular Biology, University of Kiel, Kiel D-24105, Germany.

    • Andreas Ruether
    •  & Stefan Schreiber

  6. Department of Dermatology, University of Kiel, Kiel D-24105, Germany.

    • Michael Weichenthal
    • , Enno Christophers
    •  & Tilo Henseler

  7. Department of Rheumatology, University of Toronto, Toronto, Ontario M5T 2S8, Canada.

    • Dafna Gladman

  8. Department of Medicine, Memorial University, St. John's, Newfoundland A1C 5B8, Canada.

    • Proton Rahman

  9. Celera, 1401 Harbor Bay Parkway, Alameda, California 94502, USA.

    • Steven J Schrodi
    •  & Ann B Begovich

  10. Department of Pediatrics, University of Utah, Salt Lake City, Utah 84312, USA.

    • Sampath Prahalad
    •  & Stephen L Guthery

  11. Departments of Pediatrics and, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

    • Sampath Prahalad
    • , Stephen L Guthery
    • , Judith Fischer
    •  & G Mark Lathrop

  12. Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

    • Sampath Prahalad
    • , Stephen L Guthery
    • , Wilson Liao
    •  & Pui-Yan Kwok

  13. Centre National de Génotypage, Institut Génomique, Commissariat à l'Énergie Atomique, 91057 Evry Cedex, France.

    • Judith Fischer
    • , G Mark Lathrop
    •  & Alan Menter

  14. Department of Dermatology, University of California, San Francisco, California 94153, USA.

    • Wilson Liao
    • , Pui-Yan Kwok
    •  & C Wise

  15. Department of Dermatology, Baylor University Medical Center, Dallas, Texas 75246, USA.

    • Alan Menter
    •  & James T Elder

  16. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.

    • Carol A Wise

  17. Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan 48105, USA.

    • James T Elder

  18. National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.

    • Justin Paschall

  19. Cardiovascular Research Institute and Center for Human Genetics, University of California-San Francisco, California 94143, USA.

    • Mary J Malloy
    • , Clive R Pullinger
    •  & John P Kane

  20. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

    • Amy Perlmutter
    •  & Andrew Miner

  21. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.

    • Robert W Ike

  22. Department of Dermatology, Henry Ford Hospital, Detroit, Michigan 48202, USA.

    • Henry W Lim

  23. Institute for Clinical Molecular Biology, University of Kiel, Germany.

    • Stefan Schreiber
    •  & Andre Franke

  24. Department of General Medicine, University of Kiel, Germany.

    • Stefan Schreiber

Consortia

  1. for the Collaborative Association Study of Psoriasis

Authors

  1. Search for Rajan P Nair in:

  2. Search for Kristina Callis Duffin in:

  3. Search for Cynthia Helms in:

  4. Search for Jun Ding in:

  5. Search for Philip E Stuart in:

  6. Search for David Goldgar in:

  7. Search for Johann E Gudjonsson in:

  8. Search for Yun Li in:

  9. Search for Trilokraj Tejasvi in:

  10. Search for Bing-Jian Feng in:

  11. Search for Andreas Ruether in:

  12. Search for Stefan Schreiber in:

  13. Search for Michael Weichenthal in:

  14. Search for Dafna Gladman in:

  15. Search for Proton Rahman in:

  16. Search for Steven J Schrodi in:

  17. Search for Sampath Prahalad in:

  18. Search for Stephen L Guthery in:

  19. Search for Judith Fischer in:

  20. Search for Wilson Liao in:

  21. Search for Pui-Yan Kwok in:

  22. Search for Alan Menter in:

  23. Search for G Mark Lathrop in:

  24. Search for Carol A Wise in:

  25. Search for Ann B Begovich in:

  26. Search for John J Voorhees in:

  27. Search for James T Elder in:

  28. Search for Gerald G Krueger in:

  29. Search for Anne M Bowcock in:

  30. Search for Gonçalo R Abecasis in:

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 or Gerald G Krueger or Anne M Bowcock or Gonçalo R Abecasis.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1–7 and Supplementary Figure 1

To obtain permission to re-use content from this article visit RightsLink.

About this article

Publication history

Received

Accepted

Published

DOI

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

Further reading Further reading