Mendelian randomization reveals interactions of the blood proteome and immunome in mitral valve prolapse.

Autor: Minvielle Moncla LH; Genomic Medicine Laboratory, Quebec Heart and Lung Institute, Laval University, Quebec City, QC, Canada., Briend M; Genomic Medicine Laboratory, Quebec Heart and Lung Institute, Laval University, Quebec City, QC, Canada., Sokhna Sylla M; Genomic Medicine Laboratory, Quebec Heart and Lung Institute, Laval University, Quebec City, QC, Canada., Mathieu S; Genomic Medicine Laboratory, Quebec Heart and Lung Institute, Laval University, Quebec City, QC, Canada., Rufiange A; Genomic Medicine Laboratory, Quebec Heart and Lung Institute, Laval University, Quebec City, QC, Canada., Bossé Y; Department of Molecular Medicine, Laval University, Quebec City, QC, Canada., Mathieu P; Genomic Medicine Laboratory, Quebec Heart and Lung Institute, Laval University, Quebec City, QC, Canada. patrick.mathieu@fmed.ulaval.ca.; Department of Surgery, Laval University, Quebec City, QC, Canada. patrick.mathieu@fmed.ulaval.ca.
Jazyk: angličtina
Zdroj: Communications medicine [Commun Med (Lond)] 2024 Jun 06; Vol. 4 (1), pp. 108. Date of Electronic Publication: 2024 Jun 06.
DOI: 10.1038/s43856-024-00530-x
Abstrakt: Background: Mitral valve prolapse (MVP) is a common heart disorder characterized by an excessive production of proteoglycans and extracellular matrix in mitral valve leaflets. Large-scale genome-wide association study (GWAS) underlined that MVP is heritable. The molecular underpinnings of the disease remain largely unknown.
Methods: We interrogated cross-modality data totaling more than 500,000 subjects including GWAS, 4809 molecules of the blood proteome, and genome-wide expression of mitral valves to identify candidate drivers of MVP. Data were investigated through Mendelian randomization, network analysis, ligand-receptor inference and digital cell quantification.
Results: In this study, Mendelian randomization identify that 33 blood proteins, enriched in networks for immunity, are associated with the risk of MVP. MVP- associated blood proteins are enriched in ligands for which their cognate receptors are differentially expressed in mitral valve leaflets during MVP and enriched in cardiac endothelial cells and macrophages. MVP-associated blood proteins are involved in the renewal-polarization of macrophages and regulation of adaptive immune response. Cytokine activity profiling and digital cell quantification show in MVP a shift toward cytokine signature promoting M2 macrophage polarization. Assessment of druggability identify CSF1R, CX3CR1, CCR6, IL33, MMP8, ENPEP and angiotensin receptors as actionable targets in MVP.
Conclusions: Hence, integrative analysis identifies networks of candidate molecules and cells involved in immune control and remodeling of the extracellular matrix, which drive the risk of MVP.
(© 2024. The Author(s).)
Databáze: MEDLINE
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