A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

Strange, Amy and Capon, Francesca and Spencer, Chris C. A. and Knight, Jo and Weale, Michael E. and Allen, Michael H. and Barton, Anne and Band, Gavin and Bellenguez, Céline and Bergboer, Judith G M and Blackwell, Jenefer M and Bramon, Elvira and Bumpstead, Suzannah J and Casas, Juan P and Cork, Michael J and Corvin, Aiden and Deloukas, Panos and Dilthey, Alexander and Duncanson, Audrey and Edkins, Sarah and Estivill, Xavier and Fitzgerald, Oliver and Freeman, Colin and Giardina, Emiliano and Gray, Emma and Hofer, Angelika and Hüffmeier, Ulrike and Hunt, Sarah E and Irvine, Alan D and Jankowski, Janusz and Kirby, Brian and Langford, Cordelia and Lascorz, Jesús and Leman, Joyce and Leslie, Stephen and Mallbris, Lotus and Markus, Hugh S and Mathew, Christopher G and McLean, W H Irwin and McManus, Ross and Mössner, Rotraut and Moutsianas, Loukas and Naluai, Asa T and Nestle, Frank O and Novelli, Giuseppe and Onoufriadis, Alexandros and Palmer, Colin N A and Perricone, Carlo and Pirinen, Matti and Plomin, Robert and Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Ca (2010) A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nature Genetics, 42 (11). pp. 985-990. ISSN 1061-4036

Abstract

To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10⁻⁸ and two loci with a combined P < 5 × 10⁻⁷). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10⁻⁶). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.