Importance: Hypertensive disorders in pregnancy (HDPs) are major causes of maternal and fetal morbidity and are observationally associated with future maternal risk of cardiovascular disease. However, observational results may be subject to residual confounding and bias. Objective: To investigate the association of HDPs with multiple cardiovascular diseases. Design, Setting, and Participants: A genome-wide genetic association study using mendelian randomization (MR) was performed from February 16 to March 4, 2022. Primary analysis was conducted using inverse-variance-weighted MR. Mediation analyses were performed using a multivariable MR framework. All studies included patients predominantly of European ancestry. Female-specific summary-level data from FinnGen (sixth release). Exposures: Uncorrelated (r 2<0.001) single-nucleotide variants (SNVs) were selected as instrumental variants from the FinnGen consortium summary statistics for exposures of any HDP, gestational hypertension, and preeclampsia or eclampsia. Main Outcomes and Measures: Genetic association estimates for outcomes were extracted from genome-wide association studies of 122733 cases for coronary artery disease, 34217 cases for ischemic stroke, 47309 cases for heart failure, and 60620 cases for atrial fibrillation. Results: Genetically predicted HDPs were associated with a higher risk of coronary artery disease (odds ratio [OR], 1.24; 95% CI, 1.08-1.43; P =.002); this association was evident for both gestational hypertension (OR, 1.08; 95% CI, 1.00-1.17; P =.04) and preeclampsia/eclampsia (OR, 1.06; 95% CI, 1.01-1.12; P =.03). Genetically predicted HDPs were also associated with a higher risk of ischemic stroke (OR, 1.27; 95% CI, 1.12-1.44; P = 2.87 × 10 -4). Mediation analysis revealed a partial attenuation of the effect of HDPs on coronary artery disease after adjustment for systolic blood pressure (total effect OR, 1.24; direct effect OR, 1.10; 95% CI, 1.02-1.08; P =.02) and type 2 diabetes (total effect OR, 1.24; direct effect OR, 1.16; 95% CI, 1.04-1.29; P =.008). No associations were noted between genetically predicted HDPs and heart failure (OR, 0.97; 95% CI, 0.76-1.23; P =.79) or atrial fibrillation (OR, 1.11; 95% CI, 0.65-1.88; P =.71). Conclusions and Relevance: The findings of this study provide genetic evidence supporting an association between HDPs and higher risk of coronary artery disease and stroke, which is only partially mediated by cardiometabolic factors. This supports classification of HDPs as risk factors for cardiovascular disease.
|Journal||JAMA network open|
|Publication status||Published - 17 Feb 2023|
Bibliographical noteFunding Information:
Conflict of Interest Disclosures: Dr Ardissino reported receiving grants from National Institute for Health Research (NIHR) during the conduct of the study. Dr Slob reported receiving NIHR Cambridge Biomedical Research Centre grant BRC-1215-20014 outside the submitted work. Dr Ng reported receiving grants from the British Heart Foundation and from the NIHR during the conduct of the study. No other disclosures were reported.
Funding/Support: This study was supported by the Medical Research Council (scholarship for Dr Ardissino), the NIHR (NIHR Cambridge BRC for Dr Slob, Imperial NIHR Biomedical Research Centre funding for Dr Ng), and the British Heart Foundation (RG/16/3/32175 for Dr Ng).
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