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Publication Detail
Druggable proteins influencing cardiac structure and function: implications for heart failure therapies and cancer related cardiotoxicity
  • Publication Type:
    Working discussion paper
  • Authors:
    Schmidt A, Bourfiss M, Alasiri A, Chopade S, Puyol-Anton E, Vugt MV, Laan SVD, Riele AT, Velthuis B, Franceschini N, Ruijsink B, Hingorani A, Harst PVD, Gross C, Clarkson C, Henry A, Lumbers R, Bis J, Asselbergs F, Setten JV, Finan C
  • Publication date:
    28/01/2022
  • Status:
    Published
Abstract
Dysfunction of either the right or left ventricle can lead to heart failure (HF) and subsequent morbidity and increased mortality. We performed a genome-wide association study (GWAS) of 16 measurements of biventricular function and structure obtained from cardiac magnetic resonance (CMR). We then used aggregated data from three independent plasma proteome GWAS, and performed cis- Mendelian randomization (MR) to identify proteins with a likely causal effect on biventricular traits. The subset of proteins with a robust CMR effect were prioritized through linkage with mRNA expression from the Human Protein Atlas, protein interaction data from IntAct, drug compound information from the British national formulary and ChEMBL, and by identifying plasma proteins with robust effects on HF, atrial fibrillation, non-ischemic cardiomyopathy, dilated cardiomyopathy (DCM), or coronary heart disease. In total, 33 plasma proteins were prioritised, including 25 proteins that were druggable by either an approved or developmental compound. Fifteen proteins could be mapped to compounds with a known cardiovascular indication or side-effect, including repurposing candidates with a causal effect on DCM and/or HF: IL18, IL18R, I17RA, GPC5, LAMC2, PA2GA, CD33, and SLAF7. We additionally found that 13 of the 25 druggable proteins (52%, 95%CI 0.31; 0.72) could be mapped to a compound with an oncological indication or side-effect. To further inform drug development, we performed a drug-target MR phenome-wide scan of these 33 prioritized proteins on 56 clinically relevant traits. We have identified a prioritized set of plasma proteins influencing biventricular traits, providing indispensable leads to facilitate drug development and drug repurposing for cardiac diseases, and explaining observed cardiotoxicities of several targets exploited for the treatment of cancer.
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