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Genetic Variants in ERAP 1 and ERAP 2 Associated With Immune‐Mediated Diseases Influence Protein Expression and the Isoform Profile
Author(s) -
Hanson Aimee L.,
Cuddihy Thomas,
Haynes Katelin,
Loo Dorothy,
Morton Craig J.,
Oppermann Udo,
Leo Paul,
Thomas Gethin P.,
Lê Cao KimAnh,
Kenna Tony J.,
Brown Matthew A.
Publication year - 2018
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40369
Subject(s) - biology , genetics
Objective Endoplasmic reticulum aminopeptidase 1 ( ERAP ‐1) and ERAP ‐2 , encoded on chromosome 5q15, trim endogenous peptides for HLA ‐mediated presentation to the immune system. Polymorphisms in ERAP 1 and/or ERAP 2 are strongly associated with several immune‐mediated diseases with specific HLA backgrounds, implicating altered peptide handling and presentation as prerequisites for autoreactivity against an arthritogenic peptide. Given the thorough characterization 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 were performed to detect genetic variants in ERAP 1 and ERAP 2 associated with altered total gene and isoform‐specific expression. The functional implication of a putative messenger RNA splice‐altering variant on ERAP ‐1 protein levels was validated using mass spectrometry. Results Polymorphisms associated with ankylosing spondylitis ( AS ) significantly influenced the transcript and protein expression of ERAP‐1 and ERAP‐2. Disease risk–associated polymorphisms in and around both genes were also associated with increased gene expression. Furthermore, key risk‐associated ERAP 1 variants were associated with altered transcript splicing, leading to allele‐dependent alternate expression of 2 distinct isoforms and significant differences in the type of ERAP ‐1 protein produced. Conclusion In accordance with studies demonstrating that polymorphisms that increase aminopeptidase activity predispose to immune disease, the increased risk also attributed to increased expression of ERAP 1 and ERAP 2 supports the notion of using aminopeptidase inhibition to treat AS and other ERAP ‐associated conditions.