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