Integrative Analysis of the Blood Proteome by Mendelian Randomization Reveals Regulatory Networks in Calcific Aortic Valve Disease
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".