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Integration of circulating microRNAs and transcriptome signatures identifies early‐pregnancy biomarkers of preeclampsia

BACKGROUND: MicroRNAs (miRNAs) have been implicated in the pathobiology of preeclampsia, a common hypertensive disorder of pregnancy. In a nested matched case‐control cohort within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we previously identified peripheral blood mRNA signatures rela...

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Autores principales: Mirzakhani, Hooman, Handy, Diane E., Lu, Zheng, Oppenheimer, Ben, Litonjua, Augusto A., Loscalzo, Joseph, Weiss, Scott T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10616748/
https://www.ncbi.nlm.nih.gov/pubmed/37905457
http://dx.doi.org/10.1002/ctm2.1446
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author Mirzakhani, Hooman
Handy, Diane E.
Lu, Zheng
Oppenheimer, Ben
Litonjua, Augusto A.
Loscalzo, Joseph
Weiss, Scott T.
author_facet Mirzakhani, Hooman
Handy, Diane E.
Lu, Zheng
Oppenheimer, Ben
Litonjua, Augusto A.
Loscalzo, Joseph
Weiss, Scott T.
author_sort Mirzakhani, Hooman
collection PubMed
description BACKGROUND: MicroRNAs (miRNAs) have been implicated in the pathobiology of preeclampsia, a common hypertensive disorder of pregnancy. In a nested matched case‐control cohort within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we previously identified peripheral blood mRNA signatures related to preeclampsia and vitamin D status (≤30 ng/mL) during gestation from 10 to 18 weeks, using differential expression analysis. METHODS: Using quantitative PCR arrays, we conducted profiling of circulating miRNAs at 10–18 weeks 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‐8/SVneo trophoblast cell line was used. Targets of circulating miRNA signatures in the preeclampsia mRNA signatures were identified by consensus ranking of miRNA‐target prediction scores from four sources. The connected component of target signatures was identified by mapping to the protein‐protein 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‐182‐5p, in response to a miR‐182‐5p mimic in HTR‐8/SVneo cells. RESULTS: Pregnant women with preeclampsia had 16 circulating DE miRNAs relative to normal pregnancy controls that were also DE under vitamin D insufficiency (9/16 = 56% upregulated, FDR < .05). Thirteen miRNAs (13/16 = 81.3%) were detected in HTR‐8/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‐miR‐182‐5p mimic resulted in significant reduction of its target IGF1R gene and protein expression within HTR‐8/SVneo cells. CONCLUSIONS: 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‐1, 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.
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spelling pubmed-106167482023-11-01 Integration of circulating microRNAs and transcriptome signatures identifies early‐pregnancy biomarkers of preeclampsia Mirzakhani, Hooman Handy, Diane E. Lu, Zheng Oppenheimer, Ben Litonjua, Augusto A. Loscalzo, Joseph Weiss, Scott T. Clin Transl Med Research Articles BACKGROUND: MicroRNAs (miRNAs) have been implicated in the pathobiology of preeclampsia, a common hypertensive disorder of pregnancy. In a nested matched case‐control cohort within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we previously identified peripheral blood mRNA signatures related to preeclampsia and vitamin D status (≤30 ng/mL) during gestation from 10 to 18 weeks, using differential expression analysis. METHODS: Using quantitative PCR arrays, we conducted profiling of circulating miRNAs at 10–18 weeks 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‐8/SVneo trophoblast cell line was used. Targets of circulating miRNA signatures in the preeclampsia mRNA signatures were identified by consensus ranking of miRNA‐target prediction scores from four sources. The connected component of target signatures was identified by mapping to the protein‐protein 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‐182‐5p, in response to a miR‐182‐5p mimic in HTR‐8/SVneo cells. RESULTS: Pregnant women with preeclampsia had 16 circulating DE miRNAs relative to normal pregnancy controls that were also DE under vitamin D insufficiency (9/16 = 56% upregulated, FDR < .05). Thirteen miRNAs (13/16 = 81.3%) were detected in HTR‐8/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‐miR‐182‐5p mimic resulted in significant reduction of its target IGF1R gene and protein expression within HTR‐8/SVneo cells. CONCLUSIONS: 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‐1, 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. John Wiley and Sons Inc. 2023-10-31 /pmc/articles/PMC10616748/ /pubmed/37905457 http://dx.doi.org/10.1002/ctm2.1446 Text en © 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Mirzakhani, Hooman
Handy, Diane E.
Lu, Zheng
Oppenheimer, Ben
Litonjua, Augusto A.
Loscalzo, Joseph
Weiss, Scott T.
Integration of circulating microRNAs and transcriptome signatures identifies early‐pregnancy biomarkers of preeclampsia
title Integration of circulating microRNAs and transcriptome signatures identifies early‐pregnancy biomarkers of preeclampsia
title_full Integration of circulating microRNAs and transcriptome signatures identifies early‐pregnancy biomarkers of preeclampsia
title_fullStr Integration of circulating microRNAs and transcriptome signatures identifies early‐pregnancy biomarkers of preeclampsia
title_full_unstemmed Integration of circulating microRNAs and transcriptome signatures identifies early‐pregnancy biomarkers of preeclampsia
title_short Integration of circulating microRNAs and transcriptome signatures identifies early‐pregnancy biomarkers of preeclampsia
title_sort integration of circulating micrornas and transcriptome signatures identifies early‐pregnancy biomarkers of preeclampsia
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10616748/
https://www.ncbi.nlm.nih.gov/pubmed/37905457
http://dx.doi.org/10.1002/ctm2.1446
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