Long-term cardiovascular risk in women with hypertensive disorders of pregnancy: Insights from polygenic risk scores

Introduction: The association between preeclampsia (PE) and an elevated risk of cardiovascular disease (CVD) is well documented. Recent genome-wide association studies of PE have further highlighted their possible common genetic background. We investigated how the history of hypertensive disorders of pregnancy (HDP), including the PE phenotype, and normotensive pregnancy, combined with polygenic risk scores (PRSs) for PE (PE-PRS), high systolic blood pressure (SBP-PRS), coronary artery disease (CAD-PRS) or stroke (stroke-PRS), affects the risk for CVD. Material and Methods: The study was conducted in the FinnGen cohort of 213 942 Finnish women, including 8858 women with PE, 17916 women with any HDP, and 196 026 parous controls. PE women were included in the HDP phenotype. Participants were classified based on their PRSs into three groups: low (<20%), moderate (20–80%) and high (>80%) genetic risk. Women with normotensive pregnancies and moderate PRSs served as controls. Results: Women with PE and a high genetic risk for PE, high SBP, CAD, and stroke had a significantly increased risk of CVD compared to women with normotensive pregnancies and a moderate genetic risk. The hazard ratios (HRs) for CVD were 1.87 for PE-PRS, 2.31 for SBP-PRS, 1.94 for CAD-PRS, and 2.07 for stroke-PRS, all p-values 2 × 10⁻¹⁶. A similar pattern was observed in women with any HDP. Among women with normotensive pregnancies, a high genetic risk led to only a modest increase in CVD risk. The corresponding HRs were 1.07 for PE-PRS (p = 5 × 10⁻⁵), 1.32 for SBP-PRS, 1.19 for CAD-PRS, and 1.16 for stroke-PRS (all p values 2 × 10⁻¹⁶). Across all four PRSs, the impact of PE and any HDP on CVD risk was greater than that of genetic risk alone. The elevated CVD risk persisted up to the age of 80. Conclusions: In women with PE or any HDP, a high genetic risk for PE, high SBP, CAD, and stroke further increases the overall risk of CVD. Among women with normotensive pregnancies, a high genetic risk confers only a modest increase in CVD risk. In evaluating long-term CVD risk, clinical risk assessment, including obstetric history, appears to outperform genetic risk evaluation using PRSs.