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 None., Strange A., Capon F., Spencer CCA., Knight J., Weale ME., Allen MH., Barton A., Band G., Bellenguez C., Bergboer JGM., Blackwell JM., Bramon E., Bumpstead SJ., Casas JP., Cork MJ., Corvin A., Deloukas P., Dilthey A., Duncanson A., Edkins S., Estivill X., Fitzgerald O., Freeman C., Giardina E., Gray E., Hofer A., Hüffmeier U., Hunt SE., Irvine AD., Jankowski J., Kirby B., Langford C., Lascorz J., Leman J., Leslie S., Mallbris L., Markus HS., Mathew CG., McLean WHI., McManus R., Mössner R., Moutsianas L., Naluai AT., Nestle FO., Novelli G., Onoufriadis A., Palmer CNA., Perricone C., Pirinen M., Plomin R., Potter SC., Pujol RM., Rautanen A., Riveira-Munoz E., Ryan AW., Salmhofer W., Samuelsson L., Sawcer SJ., Schalkwijk J., Smith CH., Ståhle M., Su Z., Tazi-Ahnini R., Traupe H., Viswanathan AC., Warren RB., Weger W., Wolk K., Wood N., Worthington J., Young HS., Zeeuwen PLJM., Hayday A., Burden AD., Griffiths CEM., Kere J., Reis A., McVean G., Evans DM., Brown MA., Barker JN., Peltonen L., Donnelly P., Trembath RC.
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.