TY - JOUR
T1 - Proteome- and Transcriptome-Wide Genetic Analysis Identifies Biological Pathways and Candidate Drug Targets for Preeclampsia
AU - Ardissino, Maddalena
AU - Truong, Buu
AU - Slob, Eric A.W.
AU - Schuermans, Art
AU - Yoshiji, Satoshi
AU - Morley, Alec P.
AU - Burgess, Stephen
AU - Ng, Fu Siong
AU - De Marvao, Antonio
AU - Natarajan, Pradeep
AU - Nicolaides, Kypros
AU - Gaziano, Liam
AU - Butterworth, Adam
AU - Honigberg, Michael C.
N1 - Publisher Copyright:
© 2024 American Heart Association, Inc.
PY - 2024/8/9
Y1 - 2024/8/9
N2 - 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, SH2B3, SERPINE2, RGS18, PZP, NOTUM, METAP1, MANEA, jun-D, GDF15 [growth/differentiation factor 15], FGL1, FGF5, FES, APOBR, ANP, ALDH-E2, ADAMTS13, and 3MG), 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.
AB - 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, SH2B3, SERPINE2, RGS18, PZP, NOTUM, METAP1, MANEA, jun-D, GDF15 [growth/differentiation factor 15], FGL1, FGF5, FES, APOBR, ANP, ALDH-E2, ADAMTS13, and 3MG), 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.
UR - http://www.scopus.com/inward/record.url?scp=85200972730&partnerID=8YFLogxK
U2 - 10.1161/CIRCGEN.124.004755
DO - 10.1161/CIRCGEN.124.004755
M3 - Article
C2 - 39119725
AN - SCOPUS:85200972730
SN - 1942-325X
VL - 17
SP - e004755
JO - Circulation: Genomic and Precision Medicine
JF - Circulation: Genomic and Precision Medicine
IS - 5
ER -