Key result
A proteome-wide Mendelian randomization identified 49 blood proteins causally associated with calcific aortic valve disease, with soluble IL6R showing the strongest protective association (OR 0.94).
Why the study?
Calcific aortic valve disease is characterized by fibrocalcific remodeling of the aortic valve, but the blood molecular phenome involved in the disease is unknown.
Do genetically predicted levels of specific blood proteins affect the risk of calcific aortic valve disease?
Observational (n=653,867)
Do genetically predicted levels of specific blood proteins affect the risk of calcific aortic valve disease?
Odds Ratio: 0.94 (95% CI 0.92–0.96)
p-value: p=7.99E-10
A proteome-wide Mendelian randomization study identified 49 blood proteins causally associated with calcific aortic valve disease, highlighting potential actionable targets like PCSK9, APOC3, ACE, and IL6 for drug repurposing.
Circulating proteins causally linked to CAVD via MR; hypothesis-generating and requires prospective validation before clinical translation.
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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Briend et al. (2023) conducted an observational in Calcific Aortic Valve Disease (CAVD) (n=653,867). Genetically predicted blood protein levels (e.g., soluble IL6R) vs. Reference genetic variants was evaluated on Risk of Calcific Aortic Valve Disease (per 1SD increase in soluble IL6R) (OR 0.94, 95% CI 0.92-0.96, p=7.99E-10). A proteome-wide Mendelian randomization identified 49 blood proteins causally associated with calcific aortic valve disease, with soluble IL6R showing the strongest protective association (OR 0.94).
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