Mendelian randomization of circulating proteome identifies actionable targets in heart failure

Abstract

Background: Heart failure (HF) is a prevalent cause of mortality and morbidity. The molecular drivers of HF are still largely unknown.

Results: 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.

Conclusions: 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.

Keywords: Blood protein; Druggable genome; Heart failure; Mendelian randomization; Network; Pathway.

Fig. 1

Identification of blood proteins potentially implicated in HF. Manhattan plot depicting blood proteins associated with heart failure (HF) in cis-MR analysis. The localization of the gene encoding the blood protein is represented on the x-axis, whereas the y-axis represents the -log₁₀P value for the association in MR. Red and blue dashed lines are the Bonferroni and FDR 5% threshold values respectively. Red dots are genes positively associated with the development of HF, and green dots are genes negatively associated with the development of HF

Fig. 2

Network and enrichment pathway analysis of causal blood protein candidates. A) HF causal blood protein candidates were used as seeds to generate a protein interaction network inferred from InnateDB [25] (database of 19,800 curated proteins interactions). B) Pathway enrichment analysis of the network by using the Kyoto Encyclopedia of Genes and Genomes (KEGG) [26]

Fig. 3

Cross-phenotype analysis. Cross-phenotype association analysis of HF performed by using the summary statistics data of GWAS from HERMES and the interactive cross-phenotype analysis of GWAS database (iCPAG), which includes data from the NHGRI-EBI GWAS catalog. Significance of traits was determined by the Fisher exact test

Fig. 4

Multi-trait MR. Balloon plot illustrating the multi-trait MR analysis of the 19 blood proteins as exposures, and the 31 diseases and traits as outcomes. Red and green indicates positive and negative directional effects respectively. * Indicates significance at a Bonferroni threshold; † indicates significance at FDR 5% threshold