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PMID: 20953190 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 42 ·No. 11 ·2010-11-00 ·Pages 985-90

Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2, Strange A, Capon F, Spencer CC, Knight J, Weale ME, Allen MH, Barton A, Band G, Bellenguez C, Bergboer JG, 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 WH, McManus R, Mössner R, Moutsianas L, Naluai AT, Nestle FO, Novelli G, Onoufriadis A, Palmer CN, 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 PL, Hayday A, Burden AD, Griffiths CE, Kere J, Reis A, McVean G, Evans DM, Brown MA, Barker JN, Peltonen L, Donnelly P, Trembath RC

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.

MeSH Terms
Aminopeptidases/genetics Chromosome Mapping Chromosomes, Human/genetics Chromosomes, Human, X/genetics Europe Genetic Predisposition to Disease Genetic Variation Genome-Wide Association Study HLA-C Antigens/genetics Humans Major Histocompatibility Complex/genetics Minor Histocompatibility Antigens Polymorphism, Single Nucleotide Psoriasis/genetics Reference Values Risk Assessment
Chemicals
HLA-C Antigens Minor Histocompatibility Antigens Aminopeptidases ERAP1 protein, human
Authors & Affiliations
85 authors, click to expand affiliations / ORCID
Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2
Wellcome Trust Centre for Human Genetics, Oxford, UK.
Strange Amy
Capon Francesca
Spencer Chris C A
Knight Jo
Weale Michael E
Allen Michael H
Barton Anne
Band Gavin
Bellenguez Céline
Bergboer Judith G M
Blackwell Jenefer M
Bramon Elvira
Bumpstead Suzannah J
Casas Juan P
Cork Michael J
Corvin Aiden
Deloukas Panos
Dilthey Alexander
Duncanson Audrey
Edkins Sarah
Estivill Xavier
Fitzgerald Oliver
Freeman Colin
Giardina Emiliano
Gray Emma
Hofer Angelika
Hüffmeier Ulrike
Hunt Sarah E
Irvine Alan D
Jankowski Janusz
Kirby Brian
Langford Cordelia
Lascorz Jesús
Leman Joyce
Leslie Stephen
Mallbris Lotus
Markus Hugh S
Mathew Christopher G
McLean W H Irwin
McManus Ross
Mössner Rotraut
Moutsianas Loukas
Naluai Asa T
Nestle Frank O
Novelli Giuseppe
Onoufriadis Alexandros
Palmer Colin N A
Perricone Carlo
Pirinen Matti
Plomin Robert
Potter Simon C
Pujol Ramon M
Rautanen Anna
Riveira-Munoz Eva
Ryan Anthony W
Salmhofer Wolfgang
Samuelsson Lena
Sawcer Stephen J
Schalkwijk Joost
Smith Catherine H
Ståhle Mona
Su Zhan
Tazi-Ahnini Rachid
Traupe Heiko
Viswanathan Ananth C
Warren Richard B
Weger Wolfgang
Wolk Katarina
Wood Nicholas
Worthington Jane
Young Helen S
Zeeuwen Patrick L J M
Hayday Adrian
Burden A David
Griffiths Christopher E M
Kere Juha
Reis André
McVean Gilean
Evans David M
Brown Matthew A
Barker Jonathan N
Peltonen Leena
Donnelly Peter
Trembath Richard C
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.694
Published
2010-11-00
Epub
2010-00-17
Pages
985-90
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3749730
Subset
IM
Grants
Medical Research Council · G0600705 · United Kingdom
Wellcome Trust · 085780 · United Kingdom
Wellcome Trust · 068545/Z/02 · United Kingdom
Wellcome Trust · 079643 · United Kingdom
Medical Research Council · G19/2 · United Kingdom
Medical Research Council · G0601387 · United Kingdom
Medical Research Council · G0700314 · United Kingdom
Medical Research Council · G0000934 · United Kingdom
Medical Research Council · G0901310 · United Kingdom
Wellcome Trust · 084726 · United Kingdom
Department of Health · PDA/02/06/016 · United Kingdom
Medical Research Council · G0800582 · United Kingdom
Wellcome Trust · 083948/Z/07/Z · United Kingdom
External Links
PubMed source DOI: 10.1038/ng.694 PMC Full Text View journal details
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