ERAP, KIR and HLA-C gene interaction in susceptibility to recurrent spontaneous abortion in the Polish population

Abstract

Endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 trim peptides to generate stable antigenic epitopes for their presentation by HLA class I (HLA-I) molecules to T cell receptor. By influencing the peptide repertoire of HLA-I molecules, they affect also the interactions of HLA-I with killer cell immunoglobulin-like receptors (KIRs) of natural killer (NK) cells. HLA-C is the only polymorphic HLA-I molecule present on the trophoblast.In this study we investigated the role of ERAP1 and ERAP2 polymorphisms in the context of KIR and HLA-C genes in women suffering from recurrent spontaneous abortion (RSA) in the Polish population. We used TaqMan genotyping assays for ERAP1 rs27044, rs30187, rs2287987, rs26618, rs2665 and ERAP2 rs2248374; PCR-SSP methods for KIR and HLA-C genotyping. We tested 285 women who experienced recurrent spontaneous abortion (RSA) and 319 fertile women.We observed a significant association of ERAP1 rs30187TT genotype with RSA (p = 0.02, OR = 1.89, 95%CI = 1.11–3.21), however the most striking association was found in comparison of patients and controls with ERAP1 rs30187TT and KIR Bx genotypes (p = 0.006, pcorr. = 0.036, OR = 2.40, 95%CI = 1.27–4.52). Moreover, this effect was even stronger in HLA-C2 positive patients (p = 0.0031, pcorr. = 0.019, OR = 3.46, 95%CI = 1.48–8.11). Other weaker associations of the remaining tested ERAP single nucleotide polymorphisms with RSA were also presented.In conclusion, ERAP1 rs30187TT genotype itself increased susceptibility to RSA but this effect was much stronger in patients positive for HLA-C2 and KIR Bx genotypes.