Figure 4. Precision medicine guided by human genetics.

Genetic testing of 1,000 people would identify 1–2% of individuals with a monogenic driver of risk. For example, individuals with familial hypercholesterolemia¹⁰² may derive particular benefit from lowering of LDL cholesterol levels with PCSK9 inhibitors. Second, damaging mutations in LPL⁵² or APOA5⁴⁸ increase CAD risk by preventing the clearance of dietary fat and triglyceride-rich lipoproteins from the bloodstream – this risk might be directly attenuated through use of inhibition of APOC3. Thirdly, those with a genetic predisposition to increased lipoprotein(a), i.e. at least two risk variants (at SNP sites rs10455872 or rs3798220) as previously characterized,⁷⁰ might be offered an antisense oligonucleotide to decrease circulating levels. Importantly, any such therapies would likely be incorporated in addition to guideline-based cardiovascular risk reduction therapeutics. Furthermore, confirmation that targeted PCSK9 inhibition, APOC3 inhibition, or Lp(a) reduction leads to reduction in CAD events in clinical trials is needed prior to widespread implementation. By contrast, 20% of individuals tested would be in the top quintile of a polygenic risk score – this population might be targeted for aggressive lifestyle or pharmacologic therapies beyond current treatment guidelines.