Letter | Published:

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

Nature Genetics 41, 211–215 (2009) | Download Citation

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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.

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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

    • Rafael de Cid

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

    • Rafael de Cid
    • , Eva Riveira-Munoz
    • , Patrick L J M Zeeuwen
    •  & Jason Robarge

    These authors contributed equally to this work.

Affiliations

  1. Genes and Disease Programme, Centre for Genomic Regulation (CRG) and Public Health and Epidemiology Network Biomedical Research Center (CIBERESP), 08003 Barcelona, 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, Missouri 63110, USA.

    • Jason Robarge
    • , Cynthia Helms
    •  & Anne Bowcock

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

    • Wilson Liao
    •  & Pui-Yan Kwok

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

    • Emma N Dannhauser
    •  & John A L Armour

  6. Department of Biopathology, Tor Vergata University of Rome, 00133 Rome, 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, 08003 Barcelona, 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, Washington 98195, USA.

    • Evan E Eichler

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

    • Conxi Lázaro

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

    • Gonçalo Abecasis

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

    • Xavier Estivill

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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.

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

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