Genetic Associations with Dynamic Placental Proteins Identify Causal Biomarkers for Hypertension in Pregnancy

BackgroundPreeclampsia is a complex syndrome that accounts for considerable maternal and perinatal morbidity and mortality. Despite its prevalence, no effective disease-modifying therapies are available. Maternal serum placenta-derived proteins have been in longstanding use as markers of risk for aneuploidy and placental dysfunction, but whether they have a causal contribution to preeclampsia is unknown. ObjectiveWe aimed to investigate the genetic regulation of serum placental proteins in early pregnancy and their potential causal links with preeclampsia and gestational hypertension. Study designThis study used a nested case-control design with nulliparous women enrolled in the nuMoM2b study from eight clinical sites across the United States between 2010 and 2013. The first- and second-trimester serum samples were collected, and nine proteins were measured, including vascular endothelial growth factor (VEGF), placental growth factor, endoglin, soluble fms-like tyrosine kinase-1 (sFlt-1), a disintegrin and metalloproteinase domain-containing protein 12 (ADAM-12), pregnancy-associated plasma protein A, free beta-human chorionic gonadotropin, inhibin A, and alpha-fetoprotein. This study used genome-wide association studies to discern genetic influences on these protein levels, treating proteins as outcomes. Furthermore, Mendelian randomization was used to evaluate the causal effects of these proteins on preeclampsia and gestational hypertension, and their further causal relationship with long-term hypertension, treating proteins as exposures. ResultsA total of 2,352 participants were analyzed. We discovered significant associations between the pregnancy zone protein locus and concentrations of ADAM-12 (rs6487735, P=3.03x10-22), as well as between the vascular endothelial growth factor A locus and concentrations of both VEGF (rs6921438, P=7.94x10-30) and sFlt-1 (rs4349809, P=2.89x10-12). Our Mendelian randomization analyses suggested a potential causal association between first-trimester ADAM-12 levels and gestational hypertension (odds ratio=0.78, P=8.6x10-4). We also found evidence for a potential causal effect of preeclampsia (odds ratio=1.75, P=8.3x10-3) and gestational hypertension (odds ratio=1.84, P=4.7x10-3) during the index pregnancy on the onset of hypertension 2-7 years later. The additional mediation analysis indicated that the impact of ADAM-12 on postpartum hypertension could be explained in part by its indirect effect through gestational hypertension (mediated effect=-0.15, P=0.03). ConclusionsOur study discovered significant genetic associations with placental proteins ADAM-12, VEGF, and sFlt-1, offering insights into their regulation during pregnancy. Mendelian randomization analyses demonstrated evidence of potential causal relationships between the serum levels of placental proteins, particularly ADAM-12, and gestational hypertension, potentially informing future prevention and treatment investigations.