Cardiovascular disease (CVD) remains the foremost cause of death globally, yet traditional risk models often fall short in identifying individuals at highest risk before clinical symptoms arise.
Advances in genomics are reshaping cardiovascular medicine, placing genetic markers at the core of personalized prediction and prevention strategies.
Unlike lifestyle factors, genetic variants remain stable throughout life, offering a consistent baseline to detect susceptibility long before physiological signs emerge.
Single Nucleotide Polymorphisms (SNPs): The Core of Genetic Risk
A primary focus in current research lies in single nucleotide polymorphisms (SNPs)—minute changes in the DNA sequence that may influence cardiovascular function. The 9p21 locus, for instance, remains one of the most well-documented genetic hotspots for myocardial infarction. First identified in genome-wide association studies (GWAS), variants such as rs10757278 and rs1333049 at this locus have been replicated across multiple populations, linking them to accelerated atherosclerotic plaque development.
A 2023 meta-analysis published in Circulation: Genomic and Precision Medicine reinforced that carriers of high-risk 9p21 variants exhibit nearly 30% greater relative risk for coronary artery disease (CAD), independent of cholesterol levels or blood pressure.
Polygenic Risk Scores (PRS): Translating Data Into Prognosis
While individual variants carry modest predictive power, polygenic risk scores (PRS) aggregate information from thousands of SNPs to create a more accurate portrait of inherited risk. A pivotal study by Dr. Amit Khera and colleagues at Massachusetts General Hospital, published in Nature Genetics, demonstrated that individuals in the top 5% of PRS distribution for CAD carried threefold the risk of developing disease compared to the average population.
Importantly, this elevated risk could be identified decades prior to symptom onset, enabling proactive monitoring, pharmacological intervention, or lifestyle counseling in those flagged as genetically vulnerable.
LPA Gene and Lipoprotein(a): A Distinct Pathway
Distinct from conventional lipid profiles, lipoprotein(a) [Lp(a)]—encoded by the LPA gene has emerged as a genetically determined risk factor gaining increased attention in cardiology. Elevated Lp(a) levels are primarily hereditary and resistant to modification through diet.
A 2024 update from the European Atherosclerosis Society (EAS) recommends screening for Lp(a) at least once in a lifetime, particularly in those with a family history of premature CVD. Dr. Sotirios Tsimikas, a leading figure in Lp(a) research, advocates for early genetic screening to identify individuals who may benefit from targeted therapies currently in clinical development, such as pelacarsen, an antisense oligonucleotide shown to reduce Lp(a) by over 80%.
The Role of Genetic Testing in Clinical Practice
Integrating genetic data into clinical workflows remains a complex task. Barriers include cost, access, interpretation, and ethical considerations. However, clinical guidelines are evolving.
The American College of Cardiology (ACC) has begun incorporating genetic risk factors into its recommendations for early screening, especially in cases of familial hypercholesterolemia (FH). Recent updates in the 2024 ACC/AHA guidelines now consider genotype-based risk stratification a reasonable adjunct in cases where family history and cholesterol levels fail to explain early-onset disease.
The fusion of genomics with cardiovascular medicine signals a paradigm shift toward proactive care tailored to individual DNA blueprints. As sequencing technologies become more affordable and AI-driven algorithms advance, cardiologists will increasingly rely on genetic markers to fine-tune diagnosis and treatment. Yet, with great promise comes responsibility. Medical professionals must be equipped not only to interpret genetic data but to counsel patients ethically and accurately regarding its implications.
