*3.4. Imprinting*

Overall, preeclampsia cannot be considered an imprinting disease, despite the fact that a recent study showed that imprinted genes are more di fferentially expressed in PE than other genes, with paternally expressed genes (inducing placental growth) rather down-regulated and maternally expressed genes upregulated [151]. A systematic analysis of preeclampsia placental gene expression and imprinted genes was carried out in 2017 [321], which revealed altered expression of DLX5 in human PE placentas but with a rather mild deregulation (~2 fold). To be mentioned as well, the first gene identified by positional cloning in preeclampsia, STOX1, is imprinted in specific placental cell

subtypes [322,323]. The mutation originally found in STOX1 has rather a gain-of-function e ffect [323] and in fact, overexpression of STOX1 induces a preeclamptic expression profile and a preeclamptic phenotype in cells or in mice, respectively [7,324]. To note, however, we have no evidence that Stox1 is imprinted in mice, therefore it is suspected that the mere ectopic and untimely overexpression of this factor is the cause of the disease. The idea that an imprinted gene is implicated in preeclampsia has been cleverly substantiated by Jennifer Graves as early as 1998 [325] and she gave theoretical reasons why this should be the case. The future will tell us if more examples of imprinted preeclampsia-associated genes exist in the human genome.
