The Inherited Basis of Coronary Artery Disease

Investigations of the genetic basis of coronary artery disease have led to advances in mechanistic insights, therapeutics, prevention, and risk prediction. Indeed, most contemporary medicines for coronary artery disease target pathways that promote atherosclerosis due to underpinning genetic mechanisms. Monogenic causes of coronary artery disease occur in approximately 1 out of 250 people and mostly result in massively elevated lipid levels. At the population level, hundreds of common variants with small effect sizes have even greater influence. They can be combined in polygenic risk scores that depict genetic risk in a person relative to the average in the general population. The risk among persons in the highest 5% is 3 to 5 times that among persons with an average score; relative risk derived from the polygenic risk score can be used to multiply the absolute risk derived from a clinical risk score. Key questions remain regarding the clinical value, cost-effectiveness, and implementation strategies required to integrate coronary artery disease polygenic risk scores into clinical practice.