Monogenic and Polygenic Models of Coronary Artery Disease.

Initial studies linking premature CAD with rare familial cases of elevated blood lipids highlighted high-risk monogenic contributions, predominantly presenting as familial hypercholesterolemia (FH). More commonly CAD genetic risk is a function of multiple, higher frequency variants each imparting lower magnitude of risk, which can be combined to form polygenic risk scores (PRS) conveying significant risk to individuals at the extremes. However, gaps remain in clinical validation of PRSs, most notably in non-European populations. With improved and more broadly utilized genomic sequencing technologies, the genetic underpinnings of coronary artery disease are being unraveled. As a result, polygenic risk estimation is poised to become a widely used and powerful tool in the clinical setting. While the use of PRSs to augment current clinical risk stratification for optimization of cardiovascular disease risk by lifestyle change or therapeutic targeting is promising, we await adequately powered, prospective studies, demonstrating the clinical utility of polygenic risk estimation in practice.