Contribution of fetal ANXA5 gene promoter polymorphisms to the onset of pre-eclampsia

Objective: A common haplotype M2 consisting of minor SNP alleles located in the ANXA5 gene promoter region has been described as a risk factor for various obstetric complications such as recurrent pregnancy loss, pre-eclampsia and pregnancy-related thrombophilic disorder. However, the question of whether it is the maternal or fetal genotype that contributes to the onset of these disorders remains to be resolved. Methods: We analyzed ANXA5 gene variants in the blood and placental tissues from pre-eclampsia patients and normotensive controls. ANXA5 expression was examined by qRT-PCR, Western blotting and immunostaining. Results were compared between M2 and non-M2 carriers. Results: The M2 haplotype was found to be significantly frequent in placentas from pre-eclamptic patients relative to the controls (25.5% versus 10%, P = 0.044), In contrast, no significant differences were observed in maternal blood (13.0% versus 11.3%, P = 0.597). The placental expression of ANXA5 mRNA was found to be lower in M2 carriers. When examined by Western blot and immunostaining, the ANXA5 protein levels were found to be affected more by the placental than the maternal genotype. Histological examination of the placentas from the pre-eclamptic patients demonstrated that a placental M2 haplotype correlated more closely than maternal M2 with the severity of perivillous fibrin deposition. Conclusions: Although preliminary, these results suggest that hypomorphic M2 alleles in the in placental ANXA5 promoter, whether transmitted maternally or paternally, might be an essential determinant of an increased risk of pre-eclampsia via local thrombophilia at the feto maternal interface. (C) 2013 Elsevier Ltd. All rights reserved.