Genetic associations with placental and pregnancy proteins in maternal serum identify biomarkers for hypertension in pregnancy

Abstract

Background Preeclampsia 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. Objective We aimed to investigate the genetic regulation of serum placental and pregnancy proteins in early pregnancy and their relationships with preeclampsia and gestational hypertension. Study design This study used a nested case-control design with nulliparous women enrolled in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be study from 8 clinical sites across the United States between 2010 and 2013. The first-trimester and second-trimester serum samples were collected, and 9 proteins were measured, including vascular endothelial growth factor, placental growth factor, endoglin, soluble fms-like tyrosine kinase-1, a disintegrin and metalloproteinase domain-containing protein 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 concentrations, treating proteins as outcomes. Furthermore, Mendelian randomization was used to evaluate the effects of these proteins on preeclampsia and gestational hypertension, and their further relationship with long-term hypertension, treating proteins as exposures. Results A total of 2352 participants were analyzed. We discovered significant associations between the pregnancy zone protein locus and concentrations of a disintegrin and metalloproteinase domain-containing protein 12 (rs6487735, P=3.03×10−22) and between the vascular endothelial growth factor A locus and concentrations of both vascular endothelial growth factor (rs6921438, P=7.94×10−30) and soluble fms-like tyrosine kinase-1 (rs4349809, P=2.89×10−12). Our Mendelian randomization analyses revealed an association between first-trimester a disintegrin and metalloproteinase domain-containing protein 12 concentrations and gestational hypertension (odds ratio=0.78, P<.001). We also found that preeclampsia (odds ratio=1.75, P=8.3×10−3) and gestational hypertension (odds ratio=1.84, P=.005) during the index pregnancy were associated with an increased risk of hypertension 2 to 7 years later. Conclusion Our study discovered significant genetic associations with placental proteins a disintegrin and metalloproteinase domain-containing protein 12, vascular endothelial growth factor, and soluble fms-like tyrosine kinase-1, offering insights into their regulation during pregnancy. Mendelian randomization analyses demonstrated the associations between the serum concentrations of proteins, particularly a disintegrin and metalloproteinase domain-containing protein 12, and gestational hypertension, potentially informing future prevention and treatment investigations.