Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

被引：702

作者：

Evans, David M. ^{[2
]}

Spencer, Chris C. A. ^{[1
]}

Pointon, Jennifer J. ^{[3
]}

Su, Zhan ^{[1
]}

Harvey, David ^{[3
]}

Kochan, Grazyna ^{[4
]}

Opperman, Udo ^{[4
]}

Dilthey, Alexander ^{[2
]}

Pirinen, Matti ^{[2
]}

Stone, Millicent A. ^{[5
]}

Appleton, Louise ^{[3
]}

Moutsianis, Loukas ^{[6
]}

Leslie, Stephen ^{[7
]}

Wordsworth, Tom ^{[3
]}

Kenna, Tony J. ^{[8
]}

Karaderi, Tugce ^{[3
]}

Thomas, Gethin P. ^{[8
]}

Ward, Michael M. ^{[9
]}

Weisman, Michael H. ^{[10
]}

Farrar, Claire ^{[3
]}

Bradbury, Linda A. ^{[8
]}

Danoy, Patrick ^{[8
]}

Inman, Robert D. ^{[11
]}

Maksymowych, Walter ^{[12
]}

Gladman, Dafna ^{[11
]}

Rahman, Proton ^{[13
]}

Morgan, Ann ^{[14
]}

Marzo-Ortega, Helena ^{[14
]}

Bowness, Paul ^{[3
]}

Gaffney, Karl ^{[15
]}

Gaston, J. S. Hill ^{[16
]}

Smith, Malcolm ^{[17
]}

Bruges-Armas, Jacome ^{[18
,19
]}

Couto, Ana-Rita ^{[18
]}

Sorrentino, Rosa ^{[20
]}

Paladini, Fabiana ^{[20
]}

Ferreira, Manuel A. ^{[21
]}

Xu, Huji ^{[22
]}

Liu, Yu ^{[22
]}

Jiang, Lei ^{[22
]}

Lopez-Larrea, Carlos ^{[23
]}

Diaz-Pena, Roberto ^{[23
]}

Lopez-Vazquez, Antonio ^{[23
]}

Zayats, Tetyana ^{[2
]}

Band, Gavin ^{[1
]}

Bellenguez, Celine ^{[1
]}

Blackburn, Hannah ^{[23
]}

Blackwell, Jenefer M. ^{[25
,26
]}

Bramon, Elvira ^{[24
]}

Bumpstead, Suzannah J. ^{[24
]}

机构：

[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[2] Univ Bristol, Sch Social & Community Med, Med Res Council MRC Ctr Causal Anal Translat Epid, Bristol, Avon, England

[3] Nuffield Orthopaed Ctr, Natl Inst Hlth Res Musculoskeletal Biomed Res Uni, Oxford OX3 7LD, England

[4] Univ Oxford, Struct Genom Consortium, Oxford, England

[5] Univ Bath, Bath BA2 7AY, Avon, England

[6] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

[7] Univ Oxford, Dept Clin Pharmacol, Oxford, England

[8] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia

[9] NIAMSD, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA

[10] Cedars Sinai Med Ctr, Dept Med Rheumatol, Los Angeles, CA 90048 USA

[11] Univ Toronto, Toronto, ON, Canada

[12] Univ Alberta, Dept Med, Edmonton, AB, Canada

[13] Mem Univ Newfoundland, St John, NF, Canada

[14] Univ Leeds, NIHR, Leeds Musculoskeletal Biomed Res Unit, Leeds, W Yorkshire, England

[15] Norfolk & Norwich Univ Hosp, Dept Rheumatol, Norwich, Norfolk, England

[16] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England

[17] Repatriat Gen Hosp, Adelaide, SA, Australia

[18] Hosp Santo Espirito, Serv Especializado Epidemiol & Biol Mol, Terceira, The Azores, Portugal

[19] Univ Porto, Inst Mol & Cell Biol IBMC, Genet & Arthrit Res Grp, P-4100 Oporto, Portugal

[20] Univ Roma La Sapienza, Dept Biol & Biotechnol Charles Darwin, Rome, Italy

[21] Queensland Inst Med Res, Brisbane, Qld 4006, Australia

[22] Second Mil Med Univ Hosp, Shanghai Changzheng Hosp, Dept Rheumatol & Immunol, Shanghai, Peoples R China

[23] Hosp Univ Cent Asturias, Dept Immunol, Oviedo, Spain

[24] Wellcome Trust Sanger Inst, Cambridge, England

[25] Univ Western Australia, Ctr Child Hlth Res, Telethon Inst Child Hlth Res, Perth, WA 6009, Australia

[26] Addenbrookes Hosp, Cambridge Inst Med Res, Genet & Infect Lab, Cambridge, England

[27] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England

[28] Trinity Coll Dublin, Inst Mol Med, Neuropsychiat Genet Res Grp, Dublin, Ireland

[29] Cardiff Univ, Sch Med, Dept Psychol Med, Cardiff, S Glam, Wales

[30] Wellcome Trust Res Labs, London, England

[31] Barts & London Queen Marys Sch Med & Dent, Ctr Gastroenterol, London, England

[32] St Georges Univ London, London, England

[33] Kings Coll London, Div Genet & Mol Med, London WC2R 2LS, England

[34] Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England

[35] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Dundee DD1 9SY, Scotland

[36] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England

[37] Univ Leicester, Glenfield Gen Hosp, Dept Cardiovasc Sci, Leicester, Leics, England

[38] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England

[39] Moorfields Eye Hosp NHS Fdn Trust, Glaucoma Res Unit, London, England

[40] UCL, Inst Ophthalmol, Dept Genet, London, England

[41] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England

[42] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA

来源：

NATURE GENETICS | 2011年 / 43卷 / 08期

基金：

美国国家卫生研究院; 英国医学研究理事会; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; INFLAMMATORY-BOWEL-DISEASE; GENETIC ASSOCIATION; TRIMS PRECURSORS; AMINOPEPTIDASE; RISK; HLA; POPULATION; PROMOTES; CELLS;

D O I：

10.1038/ng.873

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 x 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

引用

页码：761 / U67

页数：9

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