Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease

Abstract

Purpose of review This article will review the genetic evidence implicating ERAP1, which encodes the endoplasmic reticulum-associated amino-peptidase 1, in susceptibility to rheumatic disease. Recent findings Genetic variants and haplotypes of ERAP1 are associated with ankylosing spondylitis, psoriasis, and Behçet’s disease in people of varying ancestries. In each of these diseases, disease-associated variants of ERAP1 have been shown to interact with disease-associated class I Human Leukocyte Antigen (HLA) alleles to influence disease risk. Functionally, disease-associated missense variants of ERAP1 concertedly alter ERAP1 enzymatic function, both quantitatively and qualitatively, while other disease-associated variants influence ERAP1 expression. Therefore, ERAP1 haplotypes (or allotypes) should be examined as functional units. Biologically, this amounts to an examination of the gene regulation and function of the protein encoded by each allotype. Genetically, the relationship between disease risk and ERAP1 allotypes should be examined to determine whether allotypes or individual variants produce the most parsimonious risk models. Summary Future investigations of ERAP1 should focus on comprehensively characterizing naturally-occurring ERAP1 allotypes, examining the enzymatic function and gene expression of each allotype, and identifying specific allotypes that influence disease susceptibility.

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

“…Several studies agree to indicate the high trimming Met349/Lys528/Asp575/Arg725/Gln730 haplotype as being associated most strongly with AS risk, while the low trimming Val349/Arg528/Asn575/Gln725/Glu730 haplotype as the most protective [2,78,88]. In contrast, a report has suggested that rare hyperactive or hypoactive allotype pair combinations found in AS patients could explain the involvement of ERAP1 in the disease [79].…”

“…In particular, two of these SNPs, rs30187 (Arg528Lys) and rs27044 (Glu730Gln), reached high statistical significance for AS, as the minor alleles were robustly more frequent in AS patients than controls. Afterwards, several studies replicated these genetic associations, imputed ERAP1 haplotypes and found further associations with other SNPs mapping in the coding, UTR or intronic regions [2,78,87]. In 2011, it was proved that the association of ERAP1 with AS occurred exclusively in HLA-B27-positive patients, pointing at a gene-gene epistatic interaction [5].…”

“…Apart from a few exceptions, a higher enzymatic activity marks individual ERAP1 polymorphisms or the entire haplotypes associated with increased risk of AS (Table 1) [2,5,[78][79][80]. Several studies agree to indicate the high trimming Met349/Lys528/Asp575/Arg725/Gln730 haplotype as being associated most strongly with AS risk, while the low trimming Val349/Arg528/Asn575/Gln725/Glu730 haplotype as the most protective [2,78,88].…”

“…The most common protein variants, reported as ERAP1 allotypes, are encoded by haplotypes created by missense variant combinations of SNPs harboured in an ancestral haplotype found in humans as well as in primates [78]. The most investigated ERAP1 allotypes (from 10 to 13) [78,79] are distinguished by enzymatic functions with both qualitative (substrate preferences) and quantitative (high, intermediate and low activity variants) effects [5,64,[80][81][82]. Interestingly, some non-synonymous SNPs influence the gene expression level of ERAP1 [83].…”

A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behçet's disease in HLA-B*51 carriers

“…*Haplotype numbers according to Ombrello et al 12. These eight haplotypes represent all the coding haplotypes with frequency >1% in the Turkish controls and account for 98.8% of the haplotypes predicted with probability >0.8.…”