ImportanceHypertensive disorders of pregnancy (HDPs), including gestational hypertension and preeclampsia, are important contributors to maternal morbidity and mortality worldwide. In addition, women with HDPs face an elevated long-term risk of cardiovascular disease.ObjectiveTo identify proteins in the circulation associated with HDPs.Design, Setting, and ParticipantsTwo-sample mendelian randomization (MR) tested the associations of genetic instruments for cardiovascular disease–related proteins with gestational hypertension and preeclampsia. In downstream analyses, a systematic review of observational data was conducted to evaluate the identified proteins’ dynamics across gestation in hypertensive vs normotensive pregnancies, and phenome-wide MR analyses were performed to identify potential non-HDP–related effects associated with the prioritized proteins. Genetic association data for cardiovascular disease–related proteins were obtained from the Systematic and Combined Analysis of Olink Proteins (SCALLOP) consortium. Genetic association data for the HDPs were obtained from recent European-ancestry genome-wide association study meta-analyses for gestational hypertension and preeclampsia. Study data were analyzed October 2022 to October 2023.ExposuresGenetic instruments for 90 candidate proteins implicated in cardiovascular diseases, constructed using cis-protein quantitative trait loci (cis-pQTLs).Main Outcomes and MeasuresGestational hypertension and preeclampsia.ResultsGenetic association data for cardiovascular disease–related proteins were obtained from 21 758 participants from the SCALLOP consortium. Genetic association data for the HDPs were obtained from 393 238 female individuals (8636 cases and 384 602 controls) for gestational hypertension and 606 903 female individuals (16 032 cases and 590 871 controls) for preeclampsia. Seventy-five of 90 proteins (83.3%) had at least 1 valid cis-pQTL. Of those, 10 proteins (13.3%) were significantly associated with HDPs. Four were robust to sensitivity analyses for gestational hypertension (cluster of differentiation 40, eosinophil cationic protein [ECP], galectin 3, N-terminal pro–brain natriuretic peptide [NT-proBNP]), and 2 were robust for preeclampsia (cystatin B, heat shock protein 27 [HSP27]). Consistent with the MR findings, observational data revealed that lower NT-proBNP (0.76- to 0.88-fold difference vs no HDPs) and higher HSP27 (2.40-fold difference vs no HDPs) levels during the first trimester of pregnancy were associated with increased risk of HDPs, as were higher levels of ECP (1.60-fold difference vs no HDPs). Phenome-wide MR analyses identified 37 unique non-HDP–related protein-disease associations, suggesting potential on-target effects associated with interventions lowering HDP risk through the identified proteins.Conclusions and RelevanceStudy findings suggest genetic associations of 4 cardiovascular disease–related proteins with gestational hypertension and 2 associated with preeclampsia. Future studies are required to test the efficacy of targeting the corresponding pathways to reduce HDP risk.

中文翻译：

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循环心血管蛋白与妊娠高血压和先兆子痫的遗传关联

重要性妊娠期高血压疾病 (HDP)，包括妊娠期高血压和先兆子痫，是全球孕产妇发病和死亡的重要原因。此外，患有 HDP 的女性面临较高的心血管疾病长期风险。目的识别循环中与 HDP 相关的蛋白质。设计、设置和参与者双样本孟德尔随机化 (MR) 测试了遗传工具与心血管疾病的关联 -与妊娠高血压和先兆子痫相关的蛋白质。在下游分析中，对观察数据进行了系统回顾，以评估高血压妊娠与正常血压妊娠中已识别蛋白质的整个妊娠动态，并进行全表型 MR 分析，以确定与优先蛋白质相关的潜在非 HDP 相关效应。心血管疾病相关蛋白质的遗传关联数据来自 Olink 蛋白质系统和组合分析 (SCALLOP) 联盟。HDP 的遗传关联数据来自最近针对妊娠高血压和先兆子痫的欧洲血统全基因组关联研究荟萃分析。研究数据于 2022 年 10 月至 2023 年 10 月进行分析。Exposures 构建了与心血管疾病有关的 90 种候选蛋白质的基因仪器顺式-蛋白质数量性状位点（顺式-pQTLs）。主要结果和措施妊娠高血压和先兆子痫。结果心血管疾病相关蛋白的遗传关联数据从扇贝联盟的 21 758 名参与者中获得。HDP 的遗传关联数据来自 393 238 名妊娠高血压女性个体（8 636 例和 384 602 名对照）和 606 903 名先兆子痫女性（16 032 例和 590 871 名对照）。90 种蛋白质中的 75 种 (83.3%) 至少有 1 个有效顺式-pQTL。其中，10 种蛋白质 (13.3%) 与 HDP 显着相关。4 个对妊娠高血压的敏感性分析稳健（分化簇 40、嗜酸性粒细胞阳离子蛋白 [ECP]、半乳糖凝集素 3、N 端脑钠肽前体 [NT-proBNP]），2 个对先兆子痫的敏感性分析稳健（胱抑素 B、热休克蛋白 27 [HSP27]）。与 MR 结果一致，观察数据显示，妊娠前三个月较低的 NT-proBNP（与无 HDP 相比差异为 0.76 至 0.88 倍）和较高的 HSP27（与无 HDP 相比有 2.40 倍差异）水平与风险增加相关的 HDP，以及较高水平的 ECP（与无 HDP 相比差异 1.60 倍）。全表型 MR 分析确定了 37 种独特的非 HDP 相关蛋白质与疾病的关联，表明通过确定的蛋白质降低 HDP 风险的干预措施具有潜在的目标效应。结论和相关性研究结果表明 4 种心血管疾病相关蛋白质与疾病之间存在遗传关联。妊娠期高血压和 2 例与先兆子痫相关。未来的研究需要测试针对相应途径降低 HDP 风险的功效。