Large-Scale Functional Characterization of Low-Density Lipoprotein Receptor Gene Variants Improves Risk Assessment in Cardiovascular Disease

Limited access to functional information of genetic variants reduces the applicability of genetic tools for precision medicine applications in cardiovascular disease. We established an automated analysis platform based on multiplexed high-content imaging and derived in-depth functional data for several hundred LDLR gene variants. Residual low-density lipoprotein receptor activity of genetic variants impacted the risk for cardiovascular disease and elevated low-density lipoprotein cholesterol as well as the utilization of lipid-lowering and combination therapy. This enables increased risk stratification for carriers of LDLR gene variants and opens up new opportunities for improved diagnosis, risk assessment, and treatment selection in familial hypercholesterolemia.