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In a nested matched case\u2010control cohort within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we previously identified peripheral blood mRNA signatures related to preeclampsia and vitamin D status (\u226430\u00a0ng\/mL) during gestation from 10 to 18\u00a0weeks, using differential expression analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using quantitative PCR arrays, we conducted profiling of circulating miRNAs at 10\u201318\u00a0weeks of gestation in the same VDAART cohort to identify differentially expressed (DE) miRNAs associated with preeclampsia and vitamin D status. For the validation of the expression of circulating miRNA signatures in the placenta, the HTR\u20108\/SVneo trophoblast cell line was used. Targets of circulating miRNA signatures in the preeclampsia mRNA signatures were identified by consensus ranking of miRNA\u2010target prediction scores from four sources. The connected component of target signatures was identified by mapping to the protein\u2010protein interaction (PPI) network and hub targets were determined. As experimental validation, we examined the gene and protein expression of IGF1R, one of the key hub genes, as a target of the DE miRNA, miR\u2010182\u20105p, in response to a miR\u2010182\u20105p mimic in HTR\u20108\/SVneo cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Pregnant women with preeclampsia had 16 circulating DE miRNAs relative to normal pregnancy controls that were also DE under vitamin D insufficiency (9\/16\u00a0=\u00a056% upregulated, FDR\u00a0&lt;\u00a0.05). Thirteen miRNAs (13\/16\u00a0=\u00a081.3%) were detected in HTR\u20108\/SVneo cells. Overall, 16 DE miRNAs had 122 targets, of which 87 were unique. Network analysis demonstrated that the 32 targets of DE miRNA signatures created a connected subnetwork in the preeclampsia module with CXCL8, CXCL10, CD274, MMP9 and IGF1R having the highest connectivity and centrality degree. In an in vitro validation experiment, the introduction of an hsa\u2010miR\u2010182\u20105p mimic resulted in significant reduction of its target IGF1R gene and protein expression within HTR\u20108\/SVneo cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The integration of the circulating DE miRNA and mRNA signatures associated preeclampsia added additional insights into the subclinical molecular signature of preeclampsia. Our systems and network biology approach revealed several biological pathways, including IGF\u20101, that may play a role in the early pathophysiology of preeclampsia. These pathways and signatures also denote potential biomarkers for the early stages of preeclampsia and suggest possible preventive measures.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1446","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T09:15:15Z","timestamp":1698743715000},"source":"Crossref","is-referenced-by-count":11,"title":["Integration of circulating microRNAs and transcriptome signatures identifies early\u2010pregnancy biomarkers of preeclampsia"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2290-4436","authenticated-orcid":false,"given":"Hooman","family":"Mirzakhani","sequence":"first","affiliation":[{"name":"Channing Division of Network Medicine Department of Medicine Harvard Medical School Brigham and Women's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane E.","family":"Handy","sequence":"additional","affiliation":[{"name":"Division of 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