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. 2010 Nov;42(11):985-90.
doi: 10.1038/ng.694. Epub 2010 Oct 17.

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

Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2  1 ; Amy Strange, Francesca Capon, Chris C A Spencer, Jo Knight, Michael E Weale, Michael H Allen, Anne Barton, Gavin Band, Céline Bellenguez, Judith G M Bergboer, Jenefer M Blackwell, Elvira Bramon, Suzannah J Bumpstead, Juan P Casas, Michael J Cork, Aiden Corvin, Panos Deloukas, Alexander Dilthey, Audrey Duncanson, Sarah Edkins, Xavier Estivill, Oliver Fitzgerald, Colin Freeman, Emiliano Giardina, Emma Gray, Angelika Hofer, Ulrike Hüffmeier, Sarah E Hunt, Alan D Irvine, Janusz Jankowski, Brian Kirby, Cordelia Langford, Jesús Lascorz, Joyce Leman, Stephen Leslie, Lotus Mallbris, Hugh S Markus, Christopher G Mathew, W H Irwin McLean, Ross McManus, Rotraut Mössner, Loukas Moutsianas, Asa T Naluai, Frank O Nestle, Giuseppe Novelli, Alexandros Onoufriadis, Colin N A Palmer, Carlo Perricone, Matti Pirinen, Robert Plomin, Simon C Potter, Ramon M Pujol, Anna Rautanen, Eva Riveira-Munoz, Anthony W Ryan, Wolfgang Salmhofer, Lena Samuelsson, Stephen J Sawcer, Joost Schalkwijk, Catherine H Smith, Mona Ståhle, Zhan Su, Rachid Tazi-Ahnini, Heiko Traupe, Ananth C Viswanathan, Richard B Warren, Wolfgang Weger, Katarina Wolk, Nicholas Wood, Jane Worthington, Helen S Young, Patrick L J M Zeeuwen, Adrian Hayday, A David Burden, Christopher E M Griffiths, Juha Kere, André Reis, Gilean McVean, David M Evans, Matthew A Brown, Jonathan N Barker, Leena Peltonen, Peter Donnelly, Richard C Trembath
Affiliations

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

Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2 et al. Nat Genet. 2010 Nov.

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.

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Figures

Figure 1
Figure 1
Plot of genome wide association results. Genome wide association results from 523,067 SNPs on chromosomes 1-22 and 12,408 SNPs on the X chromosome using the additive model in SNPTEST. The −log10 (P) values are thresholded at 10−10. Regions in red are described in table 2. Regions which have been shown previously to be associated with psoriasis and which replicate in this study are highlighted in green, as described in table 1.
Figure 2
Figure 2
Regional association plots. The -log10 (P) values for SNPs at eight new loci are shown on the upper part of each plot. SNPs are coloured based on their r2 with the labeled hit SNP which has the smallest P value in the region. r2 is calculated from the 58C control data. Where more than one SNP is labeled, there is evidence for multiple signals at the locus (see text). The bottom section of each plot shows the fine scale recombination rates estimated from HapMap individuals and genes are marked by horizontal blue lines. Genes within the recombination region of the hit SNP are labeled except for 19p13, where the genes are: GLP-1, FDX1L, RAVER1, ICAM3, TKY2, CDC37, PDE4A, KEAP1, S1PR5.
Figure 3
Figure 3
Statistical interaction between ERAP1 and HLA-C genotypes. Odds ratio estimates for ERAP1 genotypes at rs27524 stratified by HLA-C genotypes at rs10484554. Odds ratios were estimated by fitting a logistic regression model which included the first principal component as a covariate and a parameter for each of the possible two-locus genotypes. Note that odds are measured relative to the most protective two-locus genotype (which by definition has an odds ratio of 1). Bars represent 95% confidence intervals calculated from the standard error of the estimates of the genotype parameters in logistic regression model.
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