Risk of preeclampsia in patients with genetic predisposition to common medical conditions: a case-control study

Gray, Kathryn J.; Kovacheva, Vesela; Mirzakhani, Hooman; Bjonnes, Andrew; Almoguera, Berta; Wilson, Melissa L.; Ingles, Sue A.; Lockwood, Charles J.; Hákonarson, Hákon; McElrath, Thomas F.; Murray, Jeffrey C.; Norwitz, Errol R.; Karumanchi, S. Ananth; Bateman, Brian T.; Keating, Brendan J.; Saxena, Richa

doi:10.1101/2020.03.04.976472

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“…One area of uncertainty is the role of specific genetic variants as determinants of disease susceptibility, although genome-wide association studies and efforts to screen functionally relevant biomarkers in human pregnancy are ongoing (11)(12)(13)(14)(15)(16)(17). In 2005, van Dijk and colleagues linked the gene encoding the Storkhead-box protein 1 transcription factor (STOX1) to preeclampsia and gestational hypertension in Dutch families (18).…”

Section: Introductionmentioning

confidence: 99%

STOX1 deficiency is associated with renin-mediated gestational hypertension and placental defects

Parchem¹,

Kanasaki²,

Lee³

et al. 2021

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The pathogenesis of preeclampsia and other hypertensive disorders of pregnancy remains poorly defined despite the substantial burden of maternal and neonatal morbidity associated with these conditions. In particular, the role of genetic variants as determinants of disease susceptibility is understudied. Storkhead-box protein 1 ( STOX1 ) was first identified as a preeclampsia risk gene through family-based genetic linkage studies in which loss-of-function variants were proposed to underlie increased preeclampsia susceptibility. We generated a genetic Stox1 loss-of-function mouse model (Stox1 KO) to evaluate whether STOX1 regulates blood pressure in pregnancy. Pregnant Stox1-KO mice developed gestational hypertension evidenced by a significant increase in blood pressure compared with WT by E17.5. While severe renal, placental, or fetal growth abnormalities were not observed, the Stox1-KO phenotype was associated with placental vascular and extracellular matrix abnormalities. Mechanistically, we found that gestational hypertension in Stox1-KO mice resulted from activation of the uteroplacental renin-angiotensin system. This mechanism was supported by showing that treatment of pregnant Stox1-KO mice with an angiotensin II receptor blocker rescued the phenotype. Our study demonstrates the utility of genetic mouse models for uncovering links between genetic variants and effector pathways implicated in the pathogenesis of hypertensive disorders of pregnancy.

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