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

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?? and two loci with a combined P < 5 × 10??). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10??). 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.

SUBMITTER: Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2

PROVIDER: S-EPMC3749730 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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

Strange Amy A Capon Francesca F Spencer Chris C A CC Knight Jo J Weale Michael E ME Allen Michael H MH Barton Anne A Band Gavin G Bellenguez Céline C Bergboer Judith G M JG Blackwell Jenefer M JM Bramon Elvira E Bumpstead Suzannah J SJ Casas Juan P JP Cork Michael J MJ Corvin Aiden A Deloukas Panos P Dilthey Alexander A Duncanson Audrey A Edkins Sarah S Estivill Xavier X Fitzgerald Oliver O Freeman Colin C Giardina Emiliano E Gray Emma E Hofer Angelika A Hüffmeier Ulrike U Hunt Sarah E SE Irvine Alan D AD Jankowski Janusz J Kirby Brian B Langford Cordelia C Lascorz Jesús J Leman Joyce J Leslie Stephen S Mallbris Lotus L Markus Hugh S HS Mathew Christopher G CG McLean W H Irwin WH McManus Ross R Mössner Rotraut R Moutsianas Loukas L Naluai Asa T AT Nestle Frank O FO Novelli Giuseppe G Onoufriadis Alexandros A Palmer Colin N A CN Perricone Carlo C Pirinen Matti M Plomin Robert R Potter Simon C SC Pujol Ramon M RM Rautanen Anna A Riveira-Munoz Eva E Ryan Anthony W AW Salmhofer Wolfgang W Samuelsson Lena L Sawcer Stephen J SJ Schalkwijk Joost J Smith Catherine H CH Ståhle Mona M Su Zhan Z Tazi-Ahnini Rachid R Traupe Heiko H Viswanathan Ananth C AC Warren Richard B RB Weger Wolfgang W Wolk Katarina K Wood Nicholas N Worthington Jane J Young Helen S HS Zeeuwen Patrick L J M PL Hayday Adrian A Burden A David AD Griffiths Christopher E M CE Kere Juha J Reis André A McVean Gilean G Evans David M DM Brown Matthew A MA Barker Jonathan N JN Peltonen Leena L Donnelly Peter P Trembath Richard C RC

Nature genetics 20101017 11

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). W ...[more]

PMID: 20953190

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Project description:A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS) and psoriatic arthritis (PSA), inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA) were genotyped with 311,398 single nucleotide polymorphisms (SNPs), and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC). The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8x10(-11), GWA scan; P = 1.8x10(-30), replication; P = 1.8x10(-39), combined; U.K. PSA: P = 6.9x10(-11)). However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13x10(-26) in U.S. cases) yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively). This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B) polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4x10(-4); U.K. PSA: P = 8.0x10(-4); IL12B:rs6887695, U.S. PS, P = 5x10(-5) and U.K. PSA, P = 1.3x10(-3)) and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001). Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP) and conserved oligomeric golgi complex component 6 (COG6) genes on chromosome 13q13 (combined P = 2x10(-6) for rs7993214; OR = 0.71), the late cornified envelope gene cluster (LCE) from the Epidermal Differentiation Complex (PSORS4) (combined P = 6.2x10(-5) for rs6701216; OR 1.45) and a region of LD at 15q21 (combined P = 2.9x10(-5) for rs3803369; OR = 1.43). This region is of interest because it harbors ubiquitin-specific protease-8 whose processed pseudogene lies upstream from HLA-C. This region of 15q21 also harbors the gene for SPPL2A (signal peptide peptidase like 2a) which activates tumor necrosis factor alpha by cleavage, triggering the expression of IL12 in human dendritic cells. We also identified a novel PSA (and potentially PS) locus on chromosome 4q27. This region harbors the interleukin 2 (IL2) and interleukin 21 (IL21) genes and was recently shown to be associated with four autoimmune diseases (Celiac disease, Type 1 diabetes, Grave's disease and Rheumatoid Arthritis).

Dataset Information

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

Publications

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

Similar Datasets

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