Proteome- and Transcriptome-Wide Genetic Analysis Identifies Biological Pathways and Candidate Drug Targets for Preeclampsia.

IF 6 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation: Genomic and Precision Medicine Pub Date : 2024-10-01 Epub Date: 2024-08-09 DOI:10.1161/CIRCGEN.124.004755

Maddalena Ardissino, Buu Truong, Eric A W Slob, Art Schuermans, Satoshi Yoshiji, Alec P Morley, Stephen Burgess, Fu Siong Ng, Antonio de Marvao, Pradeep Natarajan, Kypros Nicolaides, Liam Gaziano, Adam Butterworth, Michael C Honigberg

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引用次数: 0

Abstract

Background: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. However, the current understanding of its underlying biological pathways remains limited.

Methods: In this study, we performed a cross-platform proteome- and transcriptome-wide genetic analysis aimed at evaluating the causal relevance of >2000 circulating proteins with preeclampsia, supported by data on the expression of over 15 000 genes across 36 tissues leveraging large-scale preeclampsia genetic association data from women of European ancestry.

Results: We demonstrate genetic associations of 18 circulating proteins with preeclampsia (SULT1A1 [sulfotransferase 1A1], SH2B3 [SH2B adapter protein 3], SERPINE2 [serpin family E member 2], RGS18 [regulator of G-protein signaling 18], PZP [pregnancy zone protein], NOTUM [notum, palmitoleoyl-protein carboxylesterase], METAP1 [methionyl aminopeptidase 1], MANEA [mannosidase endo-alpha], jun-D [JunD proto-oncogene], GDF15 [growth differentiation factor 15], FGL1 [fibrinogen like 1], FGF5 [fibroblast growth factor 5], FES [FES proto-oncogene], APOBR [apolipoprotein B receptor], ANP [natriuretic peptide A], ALDH-E2 [aldehyde dehydrogenase 2 family member], ADAMTS13 [ADAM metallopeptidase with thrombospondin type 1 motif 13], and 3MG [N-methylpurine DNA glycosylase]), among which 11 were either directly or indirectly supported by gene expression data, 9 were supported by Bayesian colocalization analyses, and 5 (SERPINE2, PZP, FGF5, FES, and ANP) were supported by all lines of evidence examined. Protein interaction mapping identified potential shared biological pathways through natriuretic peptide signaling, blood pressure regulation, immune tolerance, and thrombin activity regulation.

Conclusions: This investigation identified multiple targetable proteins linked to cardiovascular, inflammatory, and coagulation pathways, with SERPINE2, PZP, FGF5, FES, and ANP identified as pivotal proteins with likely causal roles in the development of preeclampsia. The identification of these potential targets may guide the development of targeted therapies for preeclampsia.

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蛋白质组和转录组全遗传分析确定了子痫前期的生物通路和候选药物靶点。

背景：子痫前期是孕产妇和围产期发病和死亡的主要原因。然而，目前对其潜在生物学途径的了解仍然有限：在这项研究中，我们进行了一项跨平台的蛋白质组和转录组全遗传分析，旨在评估超过 2000 个循环蛋白质与子痫前期的因果关系，并利用来自欧洲血统女性的大规模子痫前期遗传关联数据，对 36 个组织中超过 15000 个基因的表达进行了数据支持：结果：我们证明了 18 种循环蛋白（SULT1A1、SH2B3、SERPINE2、RGS18、PZP、NOTUM、METAP1、MANEA、jun-D、GDF15 [生长/分化因子 15]、FGL1、FGF5、FES、APOBR、ANP、ALDH-E2、ADAMTS13、和 3MG），其中 11 个得到基因表达数据的直接或间接支持，9 个得到贝叶斯共定位分析的支持，5 个（SERPINE2、PZP、FGF5、FES 和 ANP）得到所有证据的支持。蛋白质相互作用图谱确定了通过利钠肽信号传导、血压调节、免疫耐受和凝血酶活性调节的潜在共享生物通路：这项研究发现了与心血管、炎症和凝血通路相关的多种可靶蛋白，其中SERPINE2、PZP、FGF5、FES和ANP被认为是关键蛋白，可能在子痫前期的发病中起着因果作用。这些潜在靶点的确定可为子痫前期靶向疗法的开发提供指导。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

9.20

自引率

5.40%

发文量

144

期刊介绍： Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations. Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.