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As the burden of cardiovascular disease increases in the United States, the importance of enhanced screening tools, early risk prediction, and prevention strategies grows. Novel risk scoring methods, including polygenic risk scores (PRS), may help identify patients that benefit from early intervention and risk modification. In this episode, we discuss how a PRS is calculated, how to incorporate a PRS into clinical practice, and current barriers to the equitable implementation of risk scores. In terms of frontiers in clinical genetics we also discuss the burgeoning field of pharmacogenetics and how pharmacogenetics may be used to identify responders and non-responders to certain therapies.

Join CardioNerds Dr. Jessie Holtzman (CardioNerds Academy Chief and Chief Resident and soon FIT at UCSF), Dr. Alaa Diab (CardioNerds Academy Fellow and Medicine Resident at GBMC), and student doctor Hirsh Elhence (CardioNerds Academy Intern and medical student at USC Keck School of Medicine) as they discuss frontiers in clinical genetics with Dr. Pradeep Natarajan (Director of Preventive Cardiology, Massachusetts General Hospital). Audio editing by CardioNerds Academy Intern, student doctor Akiva Rosenzveig.

This episode was developed in collaboration with the American Society of Preventive Cardiology and is supported with unrestricted educational funds from Illumina, Inc. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds.

This CardioNerds Cardiovascular Genomics series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Pearls • Notes • References

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Pearls – Frontiers in Clinical Genetics in Cardiovascular Prevention

1. For common diseases like coronary artery disease, rare mutations may confer a several-fold increased risk of disease – for instance, in familial hypercholesterolemia, a single rare mutation may confer as much as a three-fold increase in risk of coronary artery disease. However, for most common diseases, the overall cumulative impact of several common genetic variants may be greater than that of a monogenetic trait.
2. Family history is a particularly coarse predictor of CV risk, highlighting the need for polygenic risk scores. In particular, younger patients with borderline cardiovascular risk may benefit from the use of a polygenic risk score in the determination of their overall cardiovascular risk profile.
3. A polygenic risk score (PRS) is a weighted sum of several risk-conferring alleles. The weight assigned to an allele is determined by the strength of the association between the allele and CV disease, as determined by genome-wide association studies (GWAS).
4. The data used for genome-wide associated studies in cardiovascular disease have historically included populations primarily of European ancestry. However, more data is being collected from diverse patient cohorts to increase the external validity and broader applicability of such studies.
5. Pharmacogenetic polygenic risk scores may be used to predict drug efficacy and toxicity, as well as to identify biologically plausible drug targets for clinical trial design.

Show notes – Frontiers in Clinical Genetics in Cardiovascular Prevention

What is a polygenic risk score (PRS)?

• Monogenic conditions are those in which a variant in a single gene causes a pathological phenotype. For example, familial hypercholesterolemia is often the result of a mutated allele in the LDL receptor gene.
• In contrast, polygenic risk suggests that there are variants in multiple genes that all confer risk independently, each with a small individual effect size. By aggregating many variants, a risk score may be able to provide an estimate as to the degree of one’s risk of cardiovascular disease.
• By comparing the allele frequencies of genes between patients with and without cardiovascular disease, risk-conferring alleles may be identified. These studies are called genome-wide association studies (GWAS). From GWAS, PRS can then be calculated by aggregating several risk-conferring alleles.

What is the clinical utility of PRS?

• Current uses of PRS
  • Family history is a coarse predictor of CV disease. The addition of a PRS to a risk assessment may improve the clinician’s ability to risk stratify patients.
  • Calculating PRS can help identify patients who need early intervention, even in the absence of traditional risk factors (such as hypercholesterolemia or diabetes mellitus). For example, imagine a patient in the top 20^th percentile for polygenic risk with a relatively normal LDL. Despite the lack of hyperlipidemia, some evidence may suggest that a statin or aggressive lifestyle modification would lower CV risk in this patient.
  • In particular, for younger patients with borderline CV risk (as measured by traditional risk factors such as blood pressure, age, etc.), a high PRS might promote aggressive lifestyle modification or pharmacotherapy.
• Potential future uses
  • Pharmacogenomics – Understanding a patient’s genotype may help identify responders and non-responders to certain medications. For example, CYP2C19 is an enzyme that aids in the activation of Clopidogrel. Therefore, patients with a mutation in CYP2C19 may not respond as robustly to Clopidogrel and therefore alternate pharmacotherapy would be recommended.
• What are the barriers to equity?
  • Historically, GWAS studies largely enrolled patients of European ancestry. As such, the external validity of PRS outside of populations of European descent has been questioned. The NIH has prioritized capturing data from more diverse cohorts, associated with an increase in databases including patients of more varied ancestry.
  • The availability of direct-to-consumer genome sequencing kits may make calculating PRS more feasible for the broader population. However, such tests remain limited in their utility without interpretation by genetic counselors or cardiovascular geneticists.

References – Frontiers in Clinical Genetics in Cardiovascular Prevention

1. Khera AV, Chaffin M, Aragam KG, Haas ME, Roselli C, Choi SH, Natarajan P, Lander ES, Lubitz SA, Ellinor PT, Kathiresan S. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018 Sep;50(9):1219-1224. doi: 10.1038/s41588-018-0183-z. Epub 2018 Aug 13. PMID: 30104762; PMCID: PMC6128408.
2. O’Sullivan JW, Raghavan S, Marquez-Luna C, Luzum JA, Damrauer SM, Ashley EA, O’Donnell CJ, Willer CJ, Natarajan P; American Heart Association Council on Genomic and Precision Medicine; Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease. Polygenic Risk Scores for Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2022 Aug 23;146(8):e93-e118. doi: 10.1161/CIR.0000000000001077. Epub 2022 Jul 18. PMID: 35862132.