Integrating multi-modal omics to identify therapeutic atherosclerosis pathways for coronary heart disease

IntroductionUrinary metabolism breakdown products reflect metabolic changes in atherosclerosis-relevant tissues and may contain relevant therapeutic leads. We integrated data on urinary metabolism breakdown products, plasma proteins, atherosclerotic plaque tissue, and single-cell expression to identify druggable metabolic pathways for coronary heart disease (CHD). MethodsMendelian randomisation was employed to interrogate findings from independent genome-wide association studies on 954 urinary metabolism breakdown products, 1,562 unique proteins, and 181,522 CHD cases, establishing directionally concordant associations. Using the Athero-Express Biobank, concordant plasma proteins were linked to plaque vulnerability using protein and mRNA expression in plaque. Single-cell RNA sequencing data obtained from carotid plaque samples were used to test for differential expression of concordant proteins across plaque cell types. ResultsIn total, 29 urinary metabolism breakdown products associated with CHD, predominantly originating from amino acid metabolism (n=12) or unclassified origin (n=9). We identified 113 plasma proteins with directionally concordant associations with these urinary metabolism breakdown products and CHD. Of the 110 proteins available in plaque, 16 were associated with plaque vulnerability. This included positive control proteins targeted by drugs indicated for CHD, such as CAH1 (targeted by aspirin), IL6R (targeted by tocilizumab), and AT1B2 (targeted by digoxin), as well as two potential repurposing opportunities C1S (targeted by C1-esterase inhibitor and sutimlimab) and CATH (targeted by bortezomib). ConclusionWe have identified amino acid metabolism as an important contributing pathway to CHD risk and prioritised 16 proteins relevant for CHD with involvement in atherosclerotic plaques, providing important insights for drug development.