Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease: genetics

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 AS, 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 alleles to influence disease risk. Functionally, disease-associated missense variants of ERAP1 concertedly alter ERAP1 enzymatic function, both quantitatively and qualitatively, whereas 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.

Figure 1. Linkage disequilibrium (LD) among common missense variants of ERAP1 in CEU and ASN HapMap populations

The LD plots demonstrate pairwise r² values from the sets of common, missense variants of ERAP1 derived from 80 unrelated members of the CEU population (A) and 80 unrelated members of the ASN population (B). The minor allele of rs27895 had a frequency of 0.001 in the ASN population, and therefore it was excluded from LD analysis in that population. ASN, east Asian, the combined Japanese in Tokyo (JPT) and Han Chinese in Beijing (CHB) CEU, CEPH, Utah residents with ancestry from northern and western Europe.