Genetic Variants inERAP1andERAP2Associated With Immune‐Mediated Diseases Influence Protein Expression and the Isoform Profile

Abstract

ObjectiveEndoplasmic reticulum aminopeptidase 1 (ERAP‐1) andERAP‐2,encoded on chromosome 5q15, trim endogenous peptides forHLA‐mediated presentation to the immune system. Polymorphisms inERAP1and/orERAP2are strongly associated with several immune‐mediated diseases with specificHLAbackgrounds, implicating altered peptide handling and presentation as prerequisites for autoreactivity against an arthritogenic peptide. Given the thorough characterization of disease risk–associated polymorphisms that alterERAPactivity, this study aimed instead to interrogate the expression effect of chromosome 5q15 polymorphisms to determine their effect onERAPisoform and protein expression.MethodsRNAsequencing and genotyping across chromosome 5q15 were performed to detect genetic variants inERAP1andERAP2associated with altered total gene and isoform‐specific expression. The functional implication of a putative messengerRNAsplice‐altering variant onERAP‐1 protein levels was validated using mass spectrometry.ResultsPolymorphisms 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‐associatedERAP1variants were associated with altered transcript splicing, leading to allele‐dependent alternate expression of 2 distinct isoforms and significant differences in the type ofERAP‐1 protein produced.ConclusionIn accordance with studies demonstrating that polymorphisms that increase aminopeptidase activity predispose to immune disease, the increased risk also attributed to increased expression ofERAP1andERAP2supports the notion of using aminopeptidase inhibition to treatASand otherERAP‐associated conditions.