Therapeutic protein targets for cardiometabolic diseases: Mendelian randomization integrating plasma proteomes with genome-wide association data

Abstract Cardiovascular disease (CVD) is the leading cause of death worldwide, and its risk is inseparable from metabolic abnormalities. Through summary-data-based Mendelian randomization and colocalization analysis, we investigated the causal relationships between plasma proteins, 6 cardiovascular diseases, and 19 metabolic phenotypes. We identified 49 proteins genetically associated with CVDs, validated across two platforms, with 35 associated with one or more metabolic phenotypes and six having support of colocalization. These six candidate proteins were classified into three categories based on the utilization of drugs that are currently approved or in clinical trial phases, with PCSK9 already successful in drug development for CVDs and hypercholesterolemia. DUSP13B, LRIG1, APOH, INHBC, and GUSB also showed high drug potential. Further phenome-wide Mendelian randomization analysis indicated no potential side effects from targeting PCSK9 and APOH. This study revealed causal proteins for the onset of cardiovascular diseases and metabolic abnormalities, which contributed to understanding the molecular mechanisms underlying disease pathogenesis and the development of related drugs.