A novel ERAP2 haplotype structure in a Chilean population: implications for ERAP2 protein expression and preeclampsia risk

Abstract

Single nucleotide polymorphisms (SNPs) in the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene are associated with preeclampsia (PE) in different populations. rs2549782, a coding variant (N392K) that significantly affects substrate specificity, is in linkage disequilibrium (LD) with rs2248374, a marker SNP associated with ERAP2 protein expression in previously studied populations. As a result of nonsense-mediated RNA decay, ERAP2 protein is not expressed from the rs2248374 G allele. We previously reported that the fetal rs2549782 minor G allele is associated with PE in African-Americans, but not in Chileans. In this study, we found that rs2549782 was in LD with rs2248374 in African-Americans, but not in Chileans. The unexpected lack of strong LD in Chileans raised the possibility that rs2248374 could be associated with PE in the absence of an association with rs2549782. However, we found no significant association for this allele with PE in Chileans. Chileans homozygous for the rs2248374 G allele did not express 110 kDa ERAP2 protein, consistent with nonsense-mediated RNA decay, and carriers of the rs2248374 A allele did. We conclude that the Chilean ERAP2 haplotype structure allows for the expression of the major T allele of rs2549782 encoding 392N, which could impact peptide trimming and antigen presentation. Our discovery of racial differences in genetic structure and association with PE reveal heretofore unrecognized complexity of the ERAP2 locus.

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

“…This functional variant is in strong linkage with SNP rs2248374. Apart from specific ethnic peculiarities, the N392 allelic variant is almost absent in the human populations because of its co-inheritance with the rs2248374 null-allele [84,85].…”

Endoplasmic Reticulum Aminopeptidase 2, a common immunological link to adverse pregnancy outcomes and cancer clearance?

“…However, the strong linkage disequilibrium described above and ERAP2/PE association was not detected in a Chilean population, suggesting that N392 ERAP2 could be detected. However, we found that homozygosity for the T/T N392 ERAP2 (“gain-of-function”) allele is never detected in the mother or fetus in normal pregnancies in the Chilean population studied (n=528 dyads) [22]. One hypothesis to explain these observations is that “hyper” trimming capability for hydrophobic peptides alters the peptide and HLA class I repertoire in cells triggering immune activation, creating a non-permissive uterine environment for trophoblast cell/fetal survival [23].…”

Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphism Relevant to Inflammatory Disease Shapes the Peptidome of the Birdshot Chorioretinopathy-Associated HLA-A*29:02 Antigen*

“…These studies suggest common pathogenetic mechanisms involving the MHC-I bound peptidome. ERAP2, a related enzyme that acts in concert with ERAP1 (6,7), influences the susceptibility to BSCR (8), AS (although not necessarily in epistasis with HLA-B*27) (9), CrohnЈs disease (10), and preeclampsia (11)(12)(13). BSCR is a rare and severe form of bilateral posterior uveitis, showing a progressive inflammation of the choroid and retina, whose association with HLA-A*29 is the strongest for any disease and MHC.…”