Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis

Reeves, Emma, Colebatch-Bourn, Alexandra, Elliott, Tim, Edwards, Christopher J. and James, Edward (2014) Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis Proceedings of the National Academy of Sciences, 111, (49), pp. 17594-17599. (doi:10.1073/pnas.1408882111). (PMID:25422414).


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For more than 40 y, expression of HLA-B27 has been strongly associated with the chronic inflammatory disease Ankylosing Spondylitis (AS); however, the mechanisms underlying this association are still unknown. Single nucleotide polymorphisms within the aminopeptidase endoplasmic reticulum aminopeptidase 1 (ERAP1), which is essential for trimming peptides before they are presented to T cells by major histocompatibility complex (MHC) class I molecules, have been linked with disease. We show that ERAP1 is a highly polymorphic molecule comprising allotypes of single nucleotide polymorphisms. The prevalence of specific ERAP1 allotypes is different between AS cases and controls. Both chromosomal copies of ERAP1 are codominantly expressed, and analysis of allotype pairs provided clear stratification of individuals with AS versus controls. Functional analyses demonstrated that ERAP1 allotype pairs seen in AS cases were poor at generating optimal peptide ligands for binding to murine H-2K(b) and -D(b) and the AS-associated HLA-B*2705. We therefore provide strong evidence that polymorphic ERAP1 alters protein function predisposing an individual to AS via its influence on the antigen processing pathway.

Item Type: Article
Digital Object Identifier (DOI): doi:10.1073/pnas.1408882111
ISSNs: 0027-8424 (print)
Keywords: ankylosing spondylitis, ERAP1, HLA-B27, antigen presentation, antigen processing
Subjects: Q Science > QH Natural history > QH426 Genetics
Organisations: Cancer Sciences
ePrint ID: 380413
Date :
Date Event
5 November 2014Accepted/In Press
24 November 2014e-pub ahead of print
9 December 2014Published
Date Deposited: 14 Sep 2015 12:54
Last Modified: 17 Apr 2017 05:24
Further Information:Google Scholar

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