Blood proteome-wide Mendelian randomization reveals molecular pleiotropy in coronary artery disease.

Background

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Aims

Coronary artery disease (CAD) is a common cardiovascular disease characterized by the development of atheromatous plaques. Recent large-scale association study (GWAS) offers an opportunity to better understand the underpinnings of this pathology.

Methods

To investigate the underlying molecular mechanisms of CAD, we interrogated genetic association data for the blood proteome (216,063 cases and 1,246,152 controls for GWAS data and 53,480 individuals for pQTLs datasets). Data were analysed by using Mendelian randomization, inference of ligand-receptor interactions, molecular phenome-wide analysis of genetic variants and tissue-specific protein expression analysis. Pharmacological repositioning study on prioritized proteins was conducted.

Results

Using a two-tier replication MR approach with strong instrumental variables (PpQTL<5E-08) we identified 29 blood proteins associated with the risk of CAD, which were common to at least 2 exposition cohorts. Among those proteins, 17 are newly associated with CAD and were not previously reported or mapped in CAD-GWAS. CAD-associated proteome was enriched in ligands whose cognate receptors were expressed in cardiac macrophages and endothelial cells. Molecular phenome-wide association study (MolPheWAS) revealed a group of 10 blood proteins forming a pleiotropic network enriched in functions pertaining to cell migration-differentiation, inflammation and lipid metabolism. Mediation analysis identified TIMD4-APOC3, KLKB1-APOB and COLEC11-ANGPTL4 as strong putative candidate pairs involved in CAD risk. Pharmacological repositioning and tissue-specific protein expression analyses have highlighted 15 possible targets for follow-up investigations, a subset of which is specifically expressed in the liver.

Conclusions

Integrative analyses presented here provide evidence for the involvement of 29 blood proteins in CAD. Those candidate proteins take part directly or through pleiotropic effects in functions pertaining to cell migration-differentiation, inflammation and metabolism.