Researchers have identified multiple genetic markers in both maternal and fetal DNA that are strongly associated with pre-eclampsia, a dangerous hypertensive disorder of pregnancy. These discoveries are paving the way for new predictive tests and a deeper understanding of the complex maternal-fetal signaling that can lead to the life-threatening condition. By pinpointing specific genes related to blood vessel formation, blood pressure, and even body mass index, scientists are creating a more detailed map of the inherited and developmental pathways that put some pregnancies at much higher risk.
Pre-eclampsia is a major cause of maternal and infant mortality worldwide, making the quest for reliable early identification a global health priority. The condition affects 2–8% of all pregnancies and is responsible for an estimated 46,000 maternal deaths and 500,000 fetal and newborn deaths annually. It is a leading driver of preterm births and fetal growth restriction. Historically, diagnosis has relied on detecting high blood pressure and protein in the urine after 20 weeks of gestation, by which point the underlying pathology is already well-established. The new genetic findings offer the potential to shift from late-stage diagnosis to early-stage risk assessment, allowing for preventative measures and more vigilant monitoring for at-risk individuals before symptoms appear.
Understanding the Genetic Blueprint of Risk
Genetic predisposition has long been understood as a key risk factor, as women with a family history of pre-eclampsia are more likely to develop the condition themselves. However, recent large-scale studies have moved beyond familial association to identify the specific DNA variants involved. This research has revealed two distinct sources of genetic risk: variants within the mother’s own genome and, fascinatingly, variants within the fetus’s genome that influence placental function and maternal health. Maternal genetics account for an estimated 31–35% of pre-eclampsia predisposition, while the fetal genetic contribution is estimated at around 20%. These findings underscore that pre-eclampsia is not solely a maternal condition but a complex disorder arising from the intricate biological dialogue between the mother, the placenta, and the developing fetus.
Maternal and Fetal Contributions
The identification of distinct genetic loci from both mother and baby helps explain the varied presentation and severity of the disorder. Some genetic markers predispose the mother to hypertension and metabolic issues, creating a high-risk environment from the start. Other markers, originating from the fetus, can trigger a dangerous response in the mother by disrupting placental development and function. By analyzing both sets of genetic information, researchers are working to build comprehensive risk models, known as polygenic risk scores, that tally the total number of risk-associated DNA changes to provide a more personalized risk assessment.
The Fetal Gene That Triggers Maternal Disease
One of the most significant breakthroughs in pre-eclampsia research was the discovery of a genetic variant in the fetal genome with a direct, powerful effect on the mother. A large genome-wide association study (GWAS) identified a common variant near the FLT1 gene on chromosome 13 in fetal DNA that confers a substantial risk for the mother developing pre-eclampsia.
The sFlt-1 Protein Mechanism
The FLT1 gene is responsible for producing a protein called soluble fms-like tyrosine kinase-1, or sFlt-1. In a healthy pregnancy, this protein helps regulate the growth of new blood vessels. However, research has shown that the placentas of pre-eclamptic pregnancies produce an excessive amount of the sFlt-1 protein. This excess sFlt-1 is released into the mother’s bloodstream, where it acts as a potent antagonist to two crucial growth factors required for maintaining healthy blood vessels: Vascular Endothelial Growth Factor (VEGF) and Placental Growth Factor (PlGF). The sFlt-1 protein effectively traps and neutralizes these factors, preventing them from doing their job.
The resulting deficit of free VEGF and PlGF causes widespread damage to the lining of the mother’s blood vessels, a condition known as endothelial dysfunction. This systemic vascular damage is the direct cause of the main symptoms of pre-eclampsia, including hypertension and kidney damage that leads to protein in the urine. Experiments that introduced high levels of sFlt-1 into pregnant rats successfully recreated the classic signs of the disease, providing strong evidence of its causal role.
Maternal DNA and Links to Common Health Conditions
While the fetus can provide a trigger, the mother’s own genetic makeup plays a crucial role in establishing her baseline risk. An extensive international research effort, the InterPregGen study, analyzed the DNA of nearly 10,000 women with pre-eclampsia and over 157,000 control individuals. The study pinpointed several maternal genetic variants that increase the risk of developing the disorder.
The results identified DNA variants in the ZNF831 and FTO genes as significant risk factors. This finding was particularly insightful because these genes were already known to be associated with common health metrics. Variants in ZNF831 have been linked to blood pressure regulation, while the FTO gene is a well-established risk factor for a higher body mass index (BMI). This demonstrates that an inherited predisposition to general hypertension and obesity directly translates to a higher risk of developing pre-eclampsia in pregnancy. Further analysis identified other blood pressure-related genes, including MECOM, FGF5, and SH2B3, that also contribute, with some variants increasing the risk by 10–15%.
New Frontiers in Prediction and Epigenetics
This wave of genetic discovery is fueling the development of innovative diagnostic and predictive tools that could revolutionize prenatal care. One promising avenue is the analysis of cell-free RNA (cfRNA) circulating in a pregnant woman’s blood. Researchers at Stanford University identified a signature based on the expression of 18 specific genes that, when measured before 16 weeks of pregnancy, can reliably predict the later onset of pre-eclampsia. This would be the first test capable of identifying at-risk women long before any clinical symptoms appear, opening a critical window for preventative care, such as low-dose aspirin therapy.
Beyond the Genetic Code
Research is also expanding beyond the fixed DNA sequence to explore epigenetics—chemical modifications that control which genes are turned on or off. A recent study examined DNA methylation patterns and found significant differences in women who had pre-eclampsia compared to those with uncomplicated pregnancies. This suggests that environmental factors like diet or stress could influence gene activity and contribute to disease risk. These epigenetic markers could serve as another layer of biomarkers for identifying at-risk pregnancies and understanding how a mother’s environment interacts with her genetic blueprint.