Mendelian randomization of circulating proteome identifies actionable targets in heart failure

• Published in: BMC genomics Vol. 23; no. 1; pp. 1 - 12
• Main Authors: Moncla, Louis-Hippolyte Minvielle, Mathieu, Samuel, Sylla, Mame Sokhna, Bossé, Yohan, Thériault, Sébastien, Arsenault, Benoit J., Mathieu, Patrick
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 13.08.2022; BioMed Central; BMC
• Subjects: Activin; Analysis; Arteriosclerosis; Atherosclerosis; Biological effects; Blood pressure; Blood protein; Blood proteins; Candidates; Cardiovascular agents; Cardiovascular disease; Cardiovascular diseases; Causality; Cholesterol; Congestive heart failure; Control equipment; Coronary artery; Coronary artery disease; Drug development; Druggable genome; Drugs; Enrichment; Epidemiology; Fluid flow; Gene mapping; Genes; Genetic analysis; Genetic aspects; Genomes; Genomics; Glycosylation; Health aspects; Health risks; Heart attack; Heart diseases; Heart failure; Kinases; Ligands; Lipids; Mechanical stimuli; Mendelian randomization; Morbidity; Mortality; Myocardial infarction; Network; NF-κB protein; Pathway; Phenotypes; Pleiotropy; Proteins; Proteomes; Quantitative genetics; Quantitative trait loci; Randomization; Receptors; Risk analysis; Risk factors; Shear stress; Transforming growth factors
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/s12864-022-08811-2

Heart failure (HF) is a prevalent cause of mortality and morbidity. The molecular drivers of HF are still largely unknown. We aimed to identify circulating proteins causally associated with HF by leveraging genome-wide genetic association data for HF including 47,309 cases and 930,014 controls. We performed two-sample Mendelian randomization (MR) with multiple cis instruments as well as network and enrichment analysis using data from blood protein quantitative trait loci (pQTL) (2,965 blood proteins) measured in 3,301 individuals. Nineteen blood proteins were causally associated with HF, were not subject to reverse causality and were enriched in ligand-receptor and glycosylation molecules. Network pathway analysis of the blood proteins showed enrichment in NF-kappa B, TGF beta, lipid in atherosclerosis and fluid shear stress. Cross-phenotype analysis of HF identified genetic overlap with cardiovascular drugs, myocardial infarction, parental longevity and low-density cholesterol. Multi-trait MR identified causal associations between HF-associated blood proteins and cardiovascular outcomes. Multivariable MR showed that association of BAG3, MIF and APOA5 with HF were mediated by the blood pressure and coronary artery disease. According to the directional effect and biological action, 7 blood proteins are targets of existing drugs or are tractable for the development of novel therapeutics. Among the pathways, sialyl Lewis x and the activin type II receptor are potential druggable candidates. Integrative MR analyses of the blood proteins identified causally-associated proteins with HF and revealed pleiotropy of the blood proteome with cardiovascular risk factors. Some of the proteins or pathway related mechanisms could be targeted as novel treatment approach in HF.