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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2014,12,9]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>The immune system performs surveillance to identify infected or cancerous cells through recognition of small protein fragments called antigenic peptides on their surface. To do this, the peptides must be cut to a specific length by an enzyme called endoplasmic reticulum aminopeptidase 1 (ERAP1). Variation in this enzyme has recently been linked to the inflammatory rheumatic disease Ankylosing Spondylitis (AS). We have found that ERAP1 is highly polymorphic in humans and that specific combinations of ERAP1 are found in people with AS. These disease-associated combinations have a reduced ability to generate peptides for presentation at the cell surface by MHC class I molecules, including HLA-B27. Understanding this finding may allow easier identification of individuals with AS and allow stratification into prognostic groups.<\/jats:p>","DOI":"10.1073\/pnas.1408882111","type":"journal-article","created":{"date-parts":[[2014,11,24]],"date-time":"2014-11-24T23:48:51Z","timestamp":1416872931000},"page":"17594-17599","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":99,"title":["Functionally distinct\n                    <i>ERAP1<\/i>\n                    allotype combinations distinguish individuals with Ankylosing Spondylitis"],"prefix":"10.1073","volume":"111","author":[{"given":"Emma","family":"Reeves","sequence":"first","affiliation":[{"name":"Cancer Sciences Unit, Faculty of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Colebatch-Bourn","sequence":"additional","affiliation":[{"name":"National Institute for Health Research Wellcome Trust Clinical Research Facility, University Hospital Southampton National Health Service Foundation Trust, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Elliott","sequence":"additional","affiliation":[{"name":"Cancer Sciences Unit, Faculty of Medicine and"},{"name":"Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Edwards","sequence":"additional","affiliation":[{"name":"National Institute for Health Research Wellcome Trust Clinical Research Facility, University Hospital Southampton National Health Service Foundation Trust, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; and"},{"name":"Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"James","sequence":"additional","affiliation":[{"name":"Cancer Sciences Unit, Faculty of Medicine and"},{"name":"Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2014,11,24]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1038\/ng.2007.17","article-title":"Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants","volume":"39","author":"Burton PR","year":"2007","unstructured":"PR Burton, , Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet; Wellcome Trust Case Control Consortium; Australo-Anglo-American Spondylitis Consortium (TASC); Biologics in RA Genetics and Genomics Study Syndicate (BRAGGS) Steering Committee; Breast Cancer Susceptibility Collaboration (UK) 39, 1329\u20131337 (2007).","journal-title":"Nat Genet"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/ng.873","article-title":"Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility","volume":"43","author":"Evans DM","year":"2011","unstructured":"DM Evans, , Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet; Spondyloarthritis Research Consortium of Canada (SPARCC); Australo-Anglo-American Spondyloarthritis Consortium (TASC); Wellcome Trust Case Control Consortium 2 (WTCCC2) 43, 761\u2013767 (2011).","journal-title":"Nat Genet"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"4204","DOI":"10.1093\/hmg\/ddp371","article-title":"Investigating the genetic association between ERAP1 and ankylosing spondylitis","volume":"18","author":"Harvey D","year":"2009","unstructured":"D Harvey, , Investigating the genetic association between ERAP1 and ankylosing spondylitis. Hum Mol Genet 18, 4204\u20134212 (2009).","journal-title":"Hum Mol Genet"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/nature01074","article-title":"ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum","volume":"419","author":"Serwold T","year":"2002","unstructured":"T Serwold, F Gonzalez, J Kim, R Jacob, N Shastri, ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum. Nature 419, 480\u2013483 (2002).","journal-title":"Nature"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1038\/ni860","article-title":"The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8-9 residues","volume":"3","author":"York IA","year":"2002","unstructured":"IA York, , The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8-9 residues. Nat Immunol 3, 1177\u20131184 (2002).","journal-title":"Nat Immunol"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/ni1286","article-title":"The aminopeptidase ERAAP shapes the peptide repertoire displayed by major histocompatibility complex class I molecules","volume":"7","author":"Hammer GE","year":"2006","unstructured":"GE Hammer, F Gonzalez, M Champsaur, D Cado, N Shastri, The aminopeptidase ERAAP shapes the peptide repertoire displayed by major histocompatibility complex class I molecules. Nat Immunol 7, 103\u2013112 (2006).","journal-title":"Nat Immunol"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1084\/jem.20052271","article-title":"In vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules","volume":"203","author":"Yan J","year":"2006","unstructured":"J Yan, , In vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules. J Exp Med 203, 647\u2013659 (2006).","journal-title":"J Exp Med"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"9202","DOI":"10.1073\/pnas.0603095103","article-title":"Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptides in vivo and plays an important role in immunodominance","volume":"103","author":"York IA","year":"2006","unstructured":"IA York, MA Brehm, S Zendzian, CF Towne, KL Rock, Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptides in vivo and plays an important role in immunodominance. Proc Natl Acad Sci USA 103, 9202\u20139207 (2006).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.coi.2012.11.002","article-title":"ERAP1 and ankylosing spondylitis","volume":"25","author":"Keidel S","year":"2013","unstructured":"S Keidel, L Chen, J Pointon, P Wordsworth, ERAP1 and ankylosing spondylitis. Curr Opin Immunol 25, 97\u2013102 (2013).","journal-title":"Curr Opin Immunol"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1136\/ard.2008.105296","article-title":"ARTS1 polymorphisms are associated with ankylosing spondylitis in Koreans","volume":"69","author":"Choi CB","year":"2010","unstructured":"CB Choi, , ARTS1 polymorphisms are associated with ankylosing spondylitis in Koreans. Ann Rheum Dis 69, 582\u2013584 (2010).","journal-title":"Ann Rheum Dis"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1136\/annrheumdis-2012-201783","article-title":"Investigating the genetic association between ERAP1 and spondyloarthritis","volume":"72","author":"Kadi A","year":"2013","unstructured":"A Kadi, , Investigating the genetic association between ERAP1 and spondyloarthritis. 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Arthritis Rheum 60, 1317\u20131323 (2009).","journal-title":"Arthritis Rheum"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.4049\/jimmunol.1003337","article-title":"Cutting Edge: Coding single nucleotide polymorphisms of endoplasmic reticulum aminopeptidase 1 can affect antigenic peptide generation in vitro by influencing basic enzymatic properties of the enzyme","volume":"186","author":"Evnouchidou I","year":"2011","unstructured":"I Evnouchidou, , Cutting Edge: Coding single nucleotide polymorphisms of endoplasmic reticulum aminopeptidase 1 can affect antigenic peptide generation in vitro by influencing basic enzymatic properties of the enzyme. 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Nat Struct Mol Biol 18, 604\u2013613 (2011).","journal-title":"Nat Struct Mol Biol"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.molimm.2013.06.012","article-title":"ERAP1 structure, function and pathogenetic role in ankylosing spondylitis and other MHC-associated diseases","volume":"57","author":"Alvarez-Navarro C","year":"2014","unstructured":"C Alvarez-Navarro, JA L\u00f3pez de Castro, ERAP1 structure, function and pathogenetic role in ankylosing spondylitis and other MHC-associated diseases. Mol Immunol 57, 12\u201321 (2014).","journal-title":"Mol Immunol"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1084\/jem.20031982","article-title":"Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection","volume":"199","author":"Draenert R","year":"2004","unstructured":"R Draenert, , Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection. J Exp Med 199, 905\u2013915 (2004).","journal-title":"J Exp Med"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1038\/ni.2097","article-title":"Human cytomegalovirus microRNA miR-US4-1 inhibits CD8(+) T cell responses by targeting the aminopeptidase ERAP1","volume":"12","author":"Kim S","year":"2011","unstructured":"S Kim, , Human cytomegalovirus microRNA miR-US4-1 inhibits CD8(+) T cell responses by targeting the aminopeptidase ERAP1. Nat Immunol 12, 984\u2013991 (2011).","journal-title":"Nat Immunol"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/ng.2520","article-title":"Genome-wide association analysis identifies new susceptibility loci for Beh\u00e7et\u2019s disease and epistasis between HLA-B*51 and ERAP1","volume":"45","author":"Kirino Y","year":"2013","unstructured":"Y Kirino, , Genome-wide association analysis identifies new susceptibility loci for Beh\u00e7et\u2019s disease and epistasis between HLA-B*51 and ERAP1. Nat Genet 45, 202\u2013207 (2013).","journal-title":"Nat Genet"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1002\/eji.200323678","article-title":"Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling","volume":"33","author":"Bird LA","year":"2003","unstructured":"LA Bird, , Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling. Eur J Immunol 33, 748\u2013759 (2003).","journal-title":"Eur J Immunol"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1136\/annrheumdis-2012-203080","article-title":"Expression of aberrant HLA-B27 molecules is dependent on B27 dosage and peptide supply","volume":"73","author":"McHugh K","year":"2014","unstructured":"K McHugh, , Expression of aberrant HLA-B27 molecules is dependent on B27 dosage and peptide supply. Ann Rheum Dis 73, 763\u2013770 (2014).","journal-title":"Ann Rheum Dis"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.4049\/jimmunol.175.4.2438","article-title":"HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response","volume":"175","author":"Turner MJ","year":"2005","unstructured":"MJ Turner, , HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol 175, 2438\u20132448 (2005).","journal-title":"J Immunol"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.4049\/jimmunol.1002653","article-title":"Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis","volume":"186","author":"Bowness P","year":"2011","unstructured":"P Bowness, , Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. 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