{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:26:10Z","timestamp":1791930370627,"version":"4.3.4"},"reference-count":109,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"published-print":{"date-parts":[[2024,3,1]]},"abstract":"\n Importance<\/jats:title>\n Hypertensive 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.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To identify proteins in the circulation associated with HDPs.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n Two-sample mendelian randomization (MR) tested the associations of genetic instruments for cardiovascular disease\u2013related proteins with gestational hypertension and preeclampsia. In downstream analyses, a systematic review of observational data was conducted to evaluate the identified proteins\u2019 dynamics across gestation in hypertensive vs normotensive pregnancies, and phenome-wide MR analyses were performed to identify potential non-HDP\u2013related effects associated with the prioritized proteins. Genetic association data for cardiovascular disease\u2013related 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.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n \n Genetic instruments for 90 candidate proteins implicated in cardiovascular diseases, constructed using\n cis<\/jats:italic>\n -protein quantitative trait loci (\n cis<\/jats:italic>\n -pQTLs).\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Gestational hypertension and preeclampsia.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Genetic association data for cardiovascular disease\u2013related proteins were obtained from 21\u202f758 participants from the SCALLOP consortium. Genetic association data for the HDPs were obtained from 393\u202f238 female individuals (8636 cases and 384\u202f602 controls) for gestational hypertension and 606\u202f903 female individuals (16\u202f032 cases and 590\u202f871 controls) for preeclampsia. Seventy-five of 90 proteins (83.3%) had at least 1 valid\n cis<\/jats:italic>\n -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\u2013brain 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\u2013related protein-disease associations, suggesting potential on-target effects associated with interventions lowering HDP risk through the identified proteins.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n Study findings suggest genetic associations of 4 cardiovascular disease\u2013related 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamacardio.2023.4994","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T11:02:32Z","timestamp":1704279752000},"page":"209","source":"Crossref","is-referenced-by-count":40,"title":["Genetic Associations of Circulating Cardiovascular Proteins With Gestational Hypertension and Preeclampsia"],"prefix":"10.1001","volume":"9","author":[{"given":"Art","family":"Schuermans","sequence":"first","affiliation":[{"name":"Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts"},{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Boston"},{"name":"Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buu","family":"Truong","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts"},{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maddalena","family":"Ardissino","sequence":"additional","affiliation":[{"name":"BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom"},{"name":"National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohan","family":"Bhukar","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts"},{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A. 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