National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
JAMA Netw Open. 2023 Feb 1;6(2):e230034. doi: 10.1001/jamanetworkopen.2023.0034.
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.
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).
Uncorrelated (r2<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.
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.
Genetic association estimates for outcomes were extracted from genome-wide association studies of 122 733 cases for coronary artery disease, 34 217 cases for ischemic stroke, 47 309 cases for heart failure, and 60 620 cases for atrial fibrillation.
To investigate the association of HDPs with multiple cardiovascular diseases.
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).
本研究的发现提供了遗传证据，支持 HDP 与冠心病和中风风险增加之间存在关联，而这种关联部分是由心脏代谢因素介导的。这支持将 HDP 归类为心血管疾病的危险因素。
设计、环境和参与者：使用孟德尔随机化（MR）进行了一项全基因组遗传关联研究。主要分析采用逆方差加权 MR 进行。使用多变量 MR 框架进行中介分析。所有研究均包括主要为欧洲血统的患者。来自 FinnGen（第六版）的女性特异性汇总水平数据。
从 FinnGen 联盟汇总统计数据中选择不相关（r2<0.001）的单核苷酸变异（SNV）作为任何 HDP、妊娠高血压和子痫前期或子痫的工具变量。
妊娠高血压疾病（HDP）是母婴发病率的主要原因，并且与未来的母亲患心血管疾病的风险有观察性关联。然而，观察结果可能受到残余混杂因素和偏倚的影响。
从 122733 例冠心病、34217 例缺血性中风、47309 例心力衰竭和 60620 例心房颤动的全基因组关联研究中提取与结果相关的遗传关联估计值。
研究 HDP 与多种心血管疾病的关联。
遗传预测的 HDP 与冠心病风险增加相关（比值比[OR]，1.24；95%置信区间[CI]，1.08-1.43；P = .002）；这一关联在妊娠高血压（OR，1.08；95%CI，1.00-1.17；P = .04）和子痫前期/子痫（OR，1.06；95%CI，1.01-1.12；P = .03）中均明显。遗传预测的 HDP 也与缺血性中风风险增加相关（OR，1.27；95%CI，1.12-1.44；P = 2.87×10-4）。中介分析显示，在调整收缩压（总效应 OR，1.24；直接效应 OR，1.10；95%CI，1.02-1.08；P = .02）和 2 型糖尿病（总效应 OR，1.24；直接效应 OR，1.16；95%CI，1.04-1.29；P = .008）后，HDP 对冠心病的影响有所减弱。未发现遗传预测的 HDP 与心力衰竭（OR，0.97；95%CI，0.76-1.23；P = .79）或心房颤动（OR，1.11；95%CI，0.65-1.88；P = .71）之间存在关联。
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