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.

  • Letter
  • Published:

Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis

Nature Genetics volume 41, pages 211–215 (2009)Cite this article

Abstract

Psoriasis is a common inflammatory skin disease with a prevalence of 2–3% in individuals of European ancestry1. In a genome-wide search for copy number variants (CNV) using a sample pooling approach, we have identified a deletion comprising LCE3B and LCE3C, members of the late cornified envelope (LCE) gene cluster2. The absence of LCE3B and LCE3C (LCE3C_LCE3B-del) is significantly associated (P = 1.38E–08) with risk of psoriasis in 2,831 samples from Spain, The Netherlands, Italy and the United States, and in a family-based study (P = 5.4E–04). LCE3C_LCE3B-del is tagged by rs4112788 (r 2 = 0.93), which is also strongly associated with psoriasis (P < 6.6E–09). LCE3C_LCE3B-del shows epistatic effects with the HLA-Cw6 allele on the development of psoriasis in Dutch samples and multiplicative effects in the other samples. LCE expression can be induced in normal epidermis by skin barrier disruption and is strongly expressed in psoriatic lesions, suggesting that compromised skin barrier function has a role in psoriasis susceptibility.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Region of the LCE cluster containing the LCE3C_LCE3B-del associated with psoriasis.
Figure 2: Patterns of mRNA expression of LCE3C in the epidermis of psoriatic and control subjects.

Similar content being viewed by others

References

  1. Lebwohl, M. Psoriasis. Lancet 361, 1197–1204 (2003).

    Article  Google Scholar 

  2. Jackson, B. et al. Late cornified envelope family in differentiating epithelia–response to calcium and ultraviolet irradiation. J. Invest. Dermatol. 124, 1062–1070 (2005).

    Article  CAS  Google Scholar 

  3. Krueger, J.G. & Bowcock, A. Psoriasis pathophysiology: current concepts of pathogenesis. Ann. Rheum. Dis. 64 Suppl 2, ii30–ii36 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Bowcock, A.M. & Cookson, W.O. The genetics of psoriasis, psoriatic arthritis and atopic dermatitis. Hum. Mol. Genet. 13 (Spec. No. 1) R43–R55 (2004).

    Article  CAS  Google Scholar 

  6. Russell, T.J., Schultes, L.M. & Kuban, D.J. Histocompatibility (HL-A) antigens associated with psoriasis. N. Engl. J. Med. 287, 738–740 (1972).

    Article  CAS  Google Scholar 

  7. Elder, J.T. PSORS1: linking genetics and immunology. J. Invest. Dermatol. 126, 1205–1206 (2006).

    Article  CAS  Google Scholar 

  8. 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 

  9. 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 

  10. 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 

  11. 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 

  12. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).

    Article  CAS  Google Scholar 

  13. Estivill, X. & Armengol, L. Copy number variants and common disorders: filling the gaps and exploring complexity in genome-wide association studies. PLoS Genet. 3, 1787–1799 (2007).

    Article  CAS  Google Scholar 

  14. Capon, F. et al. Searching for psoriasis susceptibility genes in Italy: genome scan and evidence for a new locus on chromosome 1. J. Invest. Dermatol. 112, 32–35 (1999).

    Article  CAS  Google Scholar 

  15. Korbel, J.O. et al. Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420–426 (2007).

    Article  CAS  Google Scholar 

  16. Kidd, J.M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008).

    Article  CAS  Google Scholar 

  17. Zhao, X.P. & Elder, J.T. Positional cloning of skin-specific genes from the human epidermal differentiation complex. Genomics 45, 250–258 (1997).

    Article  CAS  Google Scholar 

  18. Chen, H. et al. Association of skin barrier genes within the PSORS4 locus is enriched in Singaporean Chinese with early-onset psoriasis. J. Invest. Dermatol. advance online publication, doi:10.1038/jid.2008.273 (11 September 2008).

  19. Asumalahti, K. et al. Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus. Hum. Mol. Genet. 11, 589–597 (2002).

    Article  CAS  Google Scholar 

  20. Nair, R.P. et al. Polymorphisms of the IL12B and IL23R genes are associated with psoriasis. J. Invest. Dermatol. 128, 1653–1661 (2008).

    Article  CAS  Google Scholar 

  21. Capon, F., Semprini, S., Dallapiccola, B. & Novelli, G. Evidence for interaction between psoriasis-susceptibility loci on chromosomes 6p21 and 1q21. Am. J. Hum. Genet. 65, 1798–1800 (1999).

    Article  CAS  Google Scholar 

  22. McCarroll, S.A. et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat. Genet. 40, 1107–1112 (2008).

    Article  CAS  Google Scholar 

  23. Aberg, K.M. et al. Co-regulation and interdependence of the mammalian epidermal permeability and antimicrobial barriers. J. Invest. Dermatol. 128, 917–925 (2008).

    Article  CAS  Google Scholar 

  24. Gonzalez, J.R. et al. Maximizing association statistics over genetic models. Genet. Epidemiol. 32, 246–254 (2008).

    Article  Google Scholar 

  25. Cordell, H.J. et al. Case/pseudocontrol analysis in genetic association studies: A unified framework for detection of genotype and haplotype associations, gene-gene and gene-environment interactions, and parent-of-origin effects. Genet. Epidemiol. 26, 167–185 (2004).

    Article  Google Scholar 

  26. Alkemade, J.A. et al. SKALP/elafin is an inducible proteinase inhibitor in human epidermal keratinocytes. J. Cell Sci. 107, 2335–2342 (1994).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge the participants in the genetic studies whose contributions made this work possible and personnel at the CeGen genotyping core facility (Barcelona node). We thank T. Henseler, S. Jenisch, M. Weichenthal and E. Christophers from the University of Kiel for making samples from Kiel, Germany available for analysis. We thank A. Poon for technical assistance, the University of California San Francisco Psoriasis Center Staff for help with subject recruitment and J. Gartlon for proofreading the manuscript. This work was supported in part by funds from the “Generalitat de Catalunya,” the Spanish Ministry of Science and Innovation and the European Commission ENGAGE Project (X.E., R.d.C., L.A., E.R.-M., G.E. and E.B.), ADIPSO (G.N.) and National Institutes for Arthritis, Musculoskeletal and Skin Diseases (A.B., J.T.E., R.N. and P.E.S.). E.R.-M. is supported by CIBERESP (Carlos III Health Institute). J.T.E. is supported by the Ann Arbor Veterans Affairs Hospital. W.L. is supported by a grant from the Dermatology Foundation.

Author information

Author notes

  1. Rafael de Cid

    Present address: Present address: Centre National de Génotypage, 91057 Evry, France.,

  2. Rafael de Cid, Eva Riveira-Munoz, Patrick L J M Zeeuwen and Jason Robarge: These authors contributed equally to this work.

Authors and Affiliations

  1. Genes and Disease Programme, Centre for Genomic Regulation (CRG) and Public Health and Epidemiology Network Biomedical Research Center (CIBERESP), Barcelona, 08003, Spain

    Rafael de Cid, Eva Riveira-Munoz, Georgia Escaramís, Ester Ballana, Lluís Armengol & Xavier Estivill

  2. Department of Dermatology and Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6525 Nijmegen, The Netherlands.,

    Patrick L J M Zeeuwen, Marijke Kamsteeg & Joost Schalkwijk

  3. Department of Genetics, Washington University School of Medicine, Saint Louis, 63110, Missouri, USA

    Jason Robarge, Cynthia Helms & Anne Bowcock

  4. University of California, San Francisco, San Francisco, 94143, California, USA

    Wilson Liao & Pui-Yan Kwok

  5. Institute of Genetics and School of Biology, University of Nottingham, Queen's Medical Centre, Nottingham, NG72RD, UK

    Emma N Dannhauser & John A L Armour

  6. Department of Biopathology, Tor Vergata University of Rome, Rome, 00133, Italy

    Emiliano Giardina & Giuseppe Novelli

  7. Department of Dermatology, University of Michigan, Michigan, 48109, USA

    Philip E Stuart, Rajan Nair & James T Elder

  8. Dermatology Service, Hospital del Mar-IMAS, Barcelona, 08003, Spain

    Gemma Martín-Ezquerra & Ramón M Pujol

  9. Department of Endocrinology and Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, 6525 Nijmegen, The Netherlands.,

    Martin den Heijer

  10. Department of Bloodtransfusion and Transplantation Immunology, Radboud University Nijmegen Medical Centre, 6525 Nijmegen, The Netherlands.,

    Irma Joosten

  11. Department of Genome Sciences, University of Washington, Seattle, 98195, Washington, USA

    Evan E Eichler

  12. Catalan Institute of Cancer, L'Hospitalet de Llobregat, Barcelona, 08907, Spain

    Conxi Lázaro

  13. Department of Biostatistics, School of Public Health, University of Michigan, Michigan, 48109, USA

    Gonçalo Abecasis

  14. Pompeu Fabra University (UPF), Barcelona, 08003, Spain

    Xavier Estivill

Authors
  1. Rafael de Cid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eva Riveira-Munoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick L J M Zeeuwen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jason Robarge
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wilson Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emma N Dannhauser
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Emiliano Giardina
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Philip E Stuart
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rajan Nair
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Cynthia Helms
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Georgia Escaramís
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ester Ballana
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gemma Martín-Ezquerra
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Martin den Heijer
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Marijke Kamsteeg
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Irma Joosten
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Evan E Eichler
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Conxi Lázaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Ramón M Pujol
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Lluís Armengol
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Gonçalo Abecasis
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. James T Elder
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Giuseppe Novelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. John A L Armour
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Pui-Yan Kwok
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Anne Bowcock
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Joost Schalkwijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Xavier Estivill
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.d.C., E.R.-M., P.L.J.M.Z. and J.R. contributed equally to this work. R.d.C., G.M.-E., R.M.P. and C.L. recruited the subjects from Spain. P.L.J.M.Z., M.K., M.d.H. and J.S. recruited the subjects from The Netherlands. E.G. and G.N. recruited the subjects from Italy. P.-Y.K., A.B., R.N., W.L. and J.T.E. recruited the subjects from the USA. R.d.C., E.R.-M., P.L.J.M.Z., J.R., W.L., E.N.D., E.G., I.J., C.H., E.B., P.E.S. and R.N. performed the genotyping and experimental work. R.d.C., L.A., G.E., G.A., P.E.S., J.S. and X.E. analyzed the data. J.S. was responsible for the design and execution of the expression studies in keratinocytes. X.E., G.N., J.T.E., E.E.E., J.A.L.A., P.K., A.B. and J.S. supervised the work. X.E. designed the study and coordinated the work. All authors contributed to the final version of the paper.

Corresponding author

Correspondence to Xavier Estivill.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3, Supplementary Tables 1–11, Supplementary Methods and Supplementary Note (PDF 906 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Cid, R., Riveira-Munoz, E., Zeeuwen, P. et al. Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat Genet 41, 211–215 (2009). https://doi.org/10.1038/ng.313

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.313

This article is cited by

Search

Advanced 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