Genetic and Conventional Risk Stratification Are Complementary for Primary Prevention of CAD

Primary prevention of coronary artery disease (CAD) needs to be initiated early in young asymptomatic individuals (20s, 30s). Current pooled cohort equation (PCE) risk stratification for CAD is based on conventional risk factors often not present until the fifth or sixth decade. Genetics accounts for 50% of risk for CAD. The number of DNA risk variants present in an individual, referred to as a polygenic risk score (PRS), can be used to risk stratify young asymptomatic individuals since the PRS is derived from DNA risk variants that are randomized at conception and can be determined at birth or anytime thereafter. The PRS does not change in one's lifetime; it has been evaluated in over 1 million individuals, and the top 20% have a threefold increased risk for CAD. The genetic risk for CAD as detected by PRS is independent of and complementary to conventional risk stratification. Genetic risk has been shown to be reduced by lowering plasma LDL-C, adopting a healthy lifestyle, and increasing physical activity. The minimal threshold required for clinical manifestations-as determined by mg per years of exposure to plasma LDL-C-is suggested to be around 5,000 mg years. This is considered the minimum clinical threshold based on a 1% incidence of myocardial infarction in the United States (US) at age 40 years and an average plasma LDL-C of 125 mg/dL, with a product of 40 × 125 resulting in 5,000 mg years. Utilizing PRS to detect candidates at increased risk for CAD while in their 30s, followed by an annual injection of a long-acting agent such as inclisiran to reduce plasma LDL-C in the range of 60 mg/dL, has the potential to delay the onset of a first myocardial infarction until age 80 years.