Individualized disease management is critical to the philosophy of precision medicine, and genetic factors are often invoked in this strategy to personalize healthcare. An example of the potential utility of PRS (Polygenic Risk Scores) in prioritizing therapeutic interventions is recent research on PRS in cardiovascular health regarding the preventive use of cholesterol-lowering therapies. According to the US Preventive Services Task Force, current guidelines for primary prevention of heart attack recommend starting statins in minor or moderate doses for individuals aged 40 to 75 who have at least one risk factor for adverse cardiovascular events (obesity, diabetes, high blood pressure, or smoking) and a 10% or higher 10-year absolute risk of adverse cardiovascular events or 7.5–10% 10-year absolute risk of adverse cardiac incidents (in this case, the final decision is made based on considering potential harms compared to the benefits of statin therapy). In primary prevention of heart attack, fewer than 2 in 100 people taking statins for five years will avoid a heart attack or stroke.
It should be noted that the PRS method in cardiovascular health does not significantly improve the overall stratification of heart attack risk in the general population. Still, combined with clinical risk assessment, it can modify individual risk in some people. In turn, it can influence the decision to start statin therapy in cases of combined risk, indicating a high threat of cardiovascular events. Numerous studies have shown that PRS in cardiovascular health helps identify some high-risk individuals who would benefit more from starting statin treatment regardless of their family history. It has been shown that patients belonging to the highest genetic risk group for cardiovascular health based on PRS have about a 30% increased risk of experiencing an adverse coronary event. After starting statin treatment in primary prevention, these individuals achieve about a 45% reduction in the relative 10-year risk of heart attack or death related to cardiovascular health. The result differs for people at medium polygenic risk, who achieve about a 25% risk reduction, while those at the lowest genetic risk show little benefit. Post hoc analyses of completed clinical trials indicate that individuals with high PRS in cardiovascular health reap the most significant relative and absolute benefits from LDL cholesterol-lowering strategies.
Finally, PRS can be helpful without personal reluctance toward preventive screening and therapeutic interventions. In the case of cardiovascular health, individuals with the highest PRS can offset a significant part of this risk by maintaining optimal lifestyle habits, reducing overall disease risk by nearly 50%. In cardiovascular health, PRS can also identify individuals who would benefit from intensive lifestyle modification, imaging surveillance (including early coronary artery CT scans), and early intensive statin therapy.
Meta-analyses of extensive studies using GWAS (Genome-Wide Association Studies) in populations of patients with cardiovascular health have identified many common genetic variants with minor effects associated with cardiovascular risk. In young people, PRS may be the best tool for stratifying cardiovascular risk in the absence of risk factors later in life. However, indications for preventive treatment in early life still require a better definition. Younger patients are less exposed to environmental factors and have not yet developed a significant burden of traditional clinical risk factors, leaving genetics the main long-term risk factor. However, exposure to lifestyle and clinical risk factors accumulates as time passes, and genetic risk becomes relatively less significant.
Similarly, when cardiovascular risk is high, or an individual has already suffered a cardiovascular event, PRS provides little information for treatment stratification. On the other hand, among middle-aged individuals with mild cardiovascular health risk factors, PRS provides additional clinical benefits to 10% of those tested. Suppose a person decides to undergo genetic testing. In that case, such arrays also include genes related to various other common conditions, including prostate, breast, and colon cancer, and therefore can provide predictive information beyond cardiovascular health risk.
Based on: AragamKG,DobbynA,JudyR,etal.Limitations of contemporary guidelines for managing patients at high genetic risk of coronary artery disease. J Am Coll Cardiol. 2020;75(22):2769-2780.
Based on: MegaJL,StitzielNO,SmithJG,etal.Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet. 2015;385 (9984):2264-2271 Khera AV, Emdin CA, Drake I, et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med. 2016;375(24):2349-2358.