3 years ago

Genetic variants in ERAP1 and ERAP2 associated with immune-mediated diseases influence protein expression and isoform profile

Katelin Haynes, Gethin P. Thomas, Thomas Cuddihy, Kim-Anh Lê Cao, Craig J. Morton, Udo Oppermann, Tony J. Kenna, Paul Leo, Matthew A. Brown, Dorothy Loo, Aimee L. Hanson
Objective The endoplasmic reticulum aminopeptidases ERAP1 and ERAP2, encoded on chromosome 5q15, trim endogenous peptides for human leukocyte antigen (HLA) mediated presentation to the immune system. Polymorphisms in ERAP1 and/or ERAP2 are strongly associated with several immune-mediated diseases with specific HLA backgrounds, implicating altered peptide handling and presentation as a prerequisite for autoreactivity against an arthritogenic peptide. Given the thorough characterisation of disease risk-associated polymorphisms that alter ERAP activity, this study aimed instead to interrogate the expression effect of chromosome 5q15 polymorphisms to determine their effect on ERAP isoform and protein expression. Methods RNA sequencing and genotyping across chromosome 5q15 was used to detect genetic variants in ERAP1 and ERAP2 associated with altered total gene and isoform-specific expression. The functional implication of a putative mRNA splice-altering variant on ERAP1 protein levels was validated using mass spectrometry. Results Polymorphisms associated with ankylosing spondylitis significantly influence the transcript and protein expression of the ERAP aminopeptidases. Disease risk-associated polymorphisms in and around both genes are also associated with increased gene expression. Furthermore, key risk-associated ERAP1 variants are associated with altered transcript splicing, leading to allele-dependent alternate expression of two distinct isoforms, and significant differences in the type of ERAP1 protein produced. Conclusions In accordance with studies demonstrating that polymorphisms that increase aminopeptidase activity predispose to immune disease, the elevated risk also attributed to increased expression of ERAP1 and ERAP2 supports the therapeutic notion of aminopeptidase inhibition to treat AS and other ERAP associated conditions. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/art.40369

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