ABSTRACT
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.
One cause of heart disease is mitral valve prolapse, where heart valve thickening leads to malfunction. Biological factors that contribute to this occurrence are largely unknown. We took advantage of different public resources and independent datasets to conduct different converging analyses to identify relevant biological factors. Using genetic variation, we implemented a technique to assess the role of circulating blood proteins on the risk of the disease. We report that blood proteins involved in the regulation of the immune response promote a dysfunctional tissue repair process of the mitral valve. This study has highlighted a contribution of blood proteins that promote excessive tissue repair leading to mitral valve dysfunction. Several of the identified proteins are potential pharmacological targets that could be singled out in future efforts to halt the progression of the disease.
