A novel ERAP 2 haplotype structure in a C hilean population: implications for ERAP 2 protein expression and preeclampsia risk

Single nucleotide polymorphisms ( SNPs ) in the endoplasmic reticulum aminopeptidase 2 ( ERAP 2 ) 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 ERAP 2 protein expression in previously studied populations. As a result of nonsense‐mediated RNA decay, ERAP 2 protein is not expressed from the rs2248374 G allele. We previously reported that the fetal rs2549782 minor G allele is associated with PE in A frican‐ A mericans, but not in C hileans. In this study, we found that rs2549782 was in LD with rs2248374 in A frican‐ A mericans, but not in C hileans. The unexpected lack of strong LD in C hileans 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 C hileans. C hileans homozygous for the rs2248374 G allele did not express 110 kDa ERAP 2 protein, consistent with nonsense‐mediated RNA decay, and carriers of the rs2248374 A allele did. We conclude that the C hilean ERAP 2 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 ERAP 2 locus.