How Preeclampsia Reveals Future Heart Disease Risk in Women
8 min read | October 2023
Groundbreaking research has revealed that women with a history of preeclampsia have up to five times the risk of developing later-life cardiovascular disease compared to those with normotensive pregnancies 1 3 . But what connects these two conditions that occur at different stages of a woman's life? The answer may lie deep within our genetic blueprint.
Preeclampsia affects 2-8% of pregnancies worldwide and is a leading cause of maternal and infant morbidity and mortality.
Preeclampsia is not simply high blood pressure during pregnancy. It's a multi-system disorder that can affect nearly every organ in the body. Clinically, it's defined by new-onset hypertension (≥140/90 mmHg) after 20 weeks of gestation accompanied by proteinuria or other signs of maternal organ dysfunction .
The endothelial dysfunction caused by preeclampsia doesn't necessarily resolve after delivery. Instead, it appears to create a persistent vulnerability that manifests years later as cardiovascular disease. Women with a history of preeclampsia have approximately double the risk of ischemic heart disease, stroke, and venous thromboembolism, and a four-fold increased risk of developing hypertension later in life .
The concept of pleiotropy—where a single gene influences multiple seemingly unrelated traits—provides a framework for understanding the genetic link between preeclampsia and cardiovascular disease. Researchers have identified several genomic regions that appear to influence susceptibility to both conditions.
For example, studies have identified variants on chromosome 2q22 containing genes (LCT, LRP1B, GCA, RND3) that are associated with preeclampsia in Australian families and were also linked to cardio-metabolic traits in other populations 1 3 . This suggests that certain genetic variants may predispose women to both preeclampsia and later cardiovascular disease.
To make sense of the growing but fragmented evidence linking genomic variation to cardiovascular disease progression after preeclampsia, researchers conducted a systematic review of the scientific literature—a rigorous approach that identifies, evaluates, and synthesizes all available research on a specific question 1 3 .
From an initial pool of 9,231 articles, only 6 studies met all criteria for inclusion in the final review after rigorous screening and quality assessment 1 2 3 .
| Genomic Category | Specific Variants | Potential Functional Significance |
|---|---|---|
| Protein-Coding Genes | RGS2, LPA, AQP3 | Regulation of vascular tone, lipid metabolism, water transport |
| MicroRNAs | miR-122-5p, miR-126-3p, miR-146a-5p, miR-206 | Post-transcriptional regulation of gene expression, inflammation |
| Epigenetic Modifications | 12 differentially methylated regions | Altered gene expression without changing DNA sequence |
The identified genes have plausible biological connections to both preeclampsia and cardiovascular disease. For example, RGS2 modulates vascular tone and blood pressure regulation, while LPA is involved in lipid metabolism and atherosclerotic processes 1 3 .
One particularly insightful study utilized data from the UK Biobank—a large-scale prospective cohort containing genetic, clinical, and lifestyle data from over 500,000 participants aged 40-69 years recruited between 2006-2010 9 .
Researchers developed polygenic risk scores (PRS) for hypertensive disorders of pregnancy (HDP-PRS). Polygenic risk scores estimate an individual's genetic predisposition to a specific condition by aggregating the effects of many genetic variants across the genome, each with small effects on disease risk 9 .
| Characteristic | High HDP-PRS | Low HDP-PRS | Statistical Significance |
|---|---|---|---|
| History of HDP | 9.8% | 4.1% | P < 0.001 |
| Hypertension at Enrollment | 38.2% | 27.6% | P < 0.001 |
| Incident ASCVD | 6.2% | 4.3% | P < 0.001 |
| Coronary Artery Disease | 4.5% | 3.1% | P = 0.002 |
These associations were replicated in an external Finnish cohort (FinnGen), strengthening the validity of the findings 9 . This suggests that the relationship between HDP and CVD is not merely causal but may reflect shared genetic underlying mechanisms.
Genomic research investigating the link between preeclampsia and cardiovascular disease relies on sophisticated laboratory techniques and analytical approaches. Here are some of the essential tools researchers use in this field:
Identifies genetic variants associated with traits/diseases. Used for discovering shared susceptibility loci for PE and CVD.
Quantifies genetic predisposition based on multiple variants. Essential for predicting individual risk of CVD following PE.
Detects epigenetic modifications across the genome. Crucial for identifying differential methylation patterns.
Uses genetic variants to infer causal relationships. Helps assess causal links between PE and subsequent CVD.
The growing understanding of genomic variation associated with cardiovascular disease progression following preeclampsia opens several promising avenues for research and clinical application:
Combining polygenic risk scores with clinical factors could help identify women at highest risk for cardiovascular disease after preeclampsia 9 .
The identified genes and pathways reveal potential targets for pharmacological intervention 1 .
Understanding genetic risk profiles could enable personalized prevention approaches based on genetic susceptibility 9 .
The journey to understanding the genomic links between preeclampsia and cardiovascular disease represents a fascinating convergence of obstetrics, cardiology, and genetics. While much remains to be discovered, current research has already revealed important insights that could transform how we approach women's cardiovascular health.
"The story of preeclampsia doesn't end with delivery—it continues throughout a woman's life. Understanding its genetic legacy is key to protecting the heart health of millions of women worldwide."
The genetic variants associated with both conditions—including genes like RGS2, LPA, and AQP3, along with microRNAs and differentially methylated regions—provide clues to the shared biological mechanisms connecting pregnancy complications with future heart disease. The development of polygenic risk scores offers promise for improved risk prediction and personalized prevention strategies.
As research continues to evolve, these genomic insights may eventually empower women with a history of preeclampsia to better understand their cardiovascular risk and take proactive steps to protect their heart health.
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