A possible role for HLA-G in development of uteroplacental acute atherosis in preeclampsia

Abstract

HLA-G, a non-classical HLA molecule expressed by extravillous trophoblasts, plays a role in the maternal immune tolerance towards fetal cells. HLA-G expression is regulated by genetic polymorphisms in the 3' untranslated region (3'UTR). Low levels of HLA-G in the maternal circulation and placental tissue are linked to preeclampsia. Our objective was to investigate whether variants of the 3'UTR of the HLA-G gene in mother and fetus are associated with acute atherosis, a pregnancy specific arterial lesion of the decidua basalis that is prevalent in preeclampsia. Paired maternal and fetal DNA samples from 83 normotensive and 83 preeclamptic pregnancies were analyzed. We sequenced the part of the HLA-G 3'UTR containing a 14-bp insertion/deletion region and seven single nucleotide polymorphisms (SNPs). Associations with acute atherosis were tested by logistic regression. The frequency of heterozygosity for the 14-bp polymorphism (Ins/Del) and the +3142 SNP (C/G) variant in the fetus are associated with acute atherosis in preeclampsia (66.7 % vs. 39.6 %, p = 0.039, and 69.0 % vs. 43.4 %, p = 0.024). Furthermore, the fetal UTR-3 haplotype, which encompasses the 14-bp deletion and the +3142G variant, is associated with acute atherosis in preeclampsia (15 % vs. 3.8 %, p = 0.016). In conclusion, HLA-G polymorphisms in the fetus are associated with acute atherosis. We hypothesize that these polymorphisms lead to altered HLA-G expression in the decidua basalis, affecting local feto-maternal immune tolerance and development of acute atherosis.

Keywords: Acute atherosis; Decidua basalis; Extravillous trophoblasts; HLA-G; HLA-G 3’UTR polymorphisms; Preeclampsia.