Integrative Analysis of the Blood Proteome by Mendelian Randomization Reveals Regulatory Networks in Calcific Aortic Valve Disease
Notice bibliographique
Résumé
Abstract Background Calcific aortic valve disease (CAVD) is a disorder characterized by fibrocalcific remodeling of the aortic valve (AV). The blood molecular phenome involved in CAVD is presently unknown. Methods We carried out a proteome-wide two-sample Mendelian randomization (MR) study to identify circulating molecules causally associated with CAVD. We queried as the exposition a large cohort of 35,559 subjects in whom 4,719 blood proteins were measured. For the outcome, we leveraged a recent GWAS for CAVD including 13,765 cases and 640,102 controls. Single-cell RNA-seq was analyzed to highlight potential pathways affected by the blood proteome. Results In MR, we identified 49 blood proteins robustly associated with the risk of CAVD. The blood proteins formed a network enriched in the immune response and ligand-receptor interactions. PCSK9, APOC3, ACE and IL6 were identified as actionable targets suitable for drug repurposing. Modulators of innate (IL6R, CNTFR, KIR2DL3-4) and adaptive (IL15RA, IGLL1, LILRA6) immune responses were associated with CAVD. Different regulators of platelets activity such as soluble GP1BA, COMP and VTN were also related to the risk of CAVD. Circulating modulators of the transforming growth factor-beta (TGF-beta) family such as ASPN, LEFTY2 and FSTL3 were associated with the risk of CAVD and their directional effects were consistent with the role of this pathway in the pathogenesis. Analysis of ligand-receptor interactions in the AV, which was inferred from single cell RNA-seq, provided further evidence that the IL6 and TGF-beta pathways are activated in CAVD. Conclusions We identified 49 blood proteins robustly and causally associated with CAVD, which were involved in the metabolism of lipids, immunity, regulation of blood pressure, platelet activation and modulation of growth factors activity. The present MR scan of the blood proteome provides a roadmap for follow-up studies and drug repurposing in CAVD. Clinical Perspective What is new? The causal blood molecular phenome is presently unknown in CAVD; herein we investigated by Mendelian randomization the causal associations between the blood proteome and the risk of CAVD. In total, 49 blood proteins were found causally associated with the risk of CAVD and were involved in the metabolism of lipids, control of the immune response, regulation of blood pressure, platelet activity and the modulation of growth factors activity. Single cell RNA-seq analysis of calcific aortic valves revealed several ligand-receptor interactions potentially affected by the blood phenome. What are the clinical implications? There is no drug therapy available to treat CAVD. Analysis of the blood proteome by Mendelian randomisation showed that in-development, approved drugs or biologics targeting PCSK9, APOC3 and ACE could be repositioned and investigated in order to treat CAVD.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».