Polygenic Risk Scores for Personalized Cardiovascular Pharmacogenomics―A Scoping Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review article provides a comprehensive overview of the integration of polygenic risk scores (PRS) into cardiovascular pharmacogenomics (PGx). It highlights the potential benefits of PRS in improving drug response prediction, reducing adverse events, and optimizing cardiovascular treatment strategies. The study systematically examines existing literature through a scoping review, analyzing 32 studies that explore PRS application in lipid-lowering therapies, antihypertensives, antiplatelets, and other cardiovascular drugs. While the findings indicate promising applications, the authors also acknowledge limitations, including ethnic biases in the studied populations, the need for improved cost-effectiveness analyses, and the lack of standardization in PRS methodologies.

The manuscript appropriately addresses PRS generalizability but could better emphasize its applicability to diverse populations. While PRS standardization is mentioned, a deeper discussion on harmonization efforts would be beneficial. The section on real-world implementation could also be expanded with clinical validation examples.

Future research should focus on multi-population validation and improved PRS calculation methods. Integrating PRS with other biomarkers like transcriptomics could enhance predictive power. Additionally, addressing PRS performance variability at the individual level would strengthen clinical applicability.

PRS is a useful tool but should be integrated into a broader risk assessment, considering environmental and clinical factors. Recent findings by Abramowitz et al. (2024) highlight inconsistencies in individual risk estimates despite strong population-level performance. A discussion on PRS uncertainty and its implications for clinical decision-making should be included.

Overall, this manuscript is well-executed and valuable. Enhancing discussions on standardization, real-world applications, and PRS limitations at the individual level would further improve its impact.

The tables in the manuscript should be displayed in the 'landscape' frame.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

I have peer-reviewed the manuscript "Polygenic Risk Scores for Personalized Cardiovascular Pharmacogenomics" submitted to Sci. Pharm Journal – MDPI. I have provided my review report as an overview, comments, and suggestions below.

Overview: The manuscript presents a comprehensive scoping review on the application of polygenic risk scores (PRS) in the pharmacogenomics (PGx) of cardiovascular disease (CVD). The authors analyze how PRS can be integrated into clinical decision-making, particularly in optimizing drug efficacy, minimizing adverse effects, and assessing cost-effectiveness. The manuscript adheres to the PRISMA-ScR guidelines and reviews 32 studies covering lipid-lowering therapies, antihypertensives, rate control agents, antiarrhythmics, antiplatelets, and anti-inflammatory drugs.

Strengths: The authors systematically reviewed the studies from reputable databases, ensuring a broad and relevant scope, and effectively addressed the current gap in integrating PRS into cardiovascular PGx. The inclusion of study selection criteria, data extraction processes, and outcome measures enhanced transparency and reproducibility. The findings highlight the potential of PRS in improving personalized medicine for CVD treatment. The discussion acknowledges the lack of representation of non-European populations in PRS studies, emphasizing the need for broader genetic inclusion.

Questions:

1. While the authors acknowledge study heterogeneity as a barrier to formal meta-analysis, what is their opinion on an attempt at pooled effect estimates for selected subgroups that would strengthen the manuscript?
2. The manuscript did not elaborate on the challenges of PRS standardization across different studies and propose potential solutions, how do the authors address these challenges?
3. While the manuscript discusses the promise of PRS, it does not delve deeply into the regulatory, ethical, and logistical challenges of incorporating PRS into routine clinical practice. How do the authors can address the Clinical Implementation Challenges?
4. Why does the discussion on cost-effectiveness remain superficial? More details on economic modeling and its impact on healthcare policy would enhance the manuscript’s applicability.
5. Tables summarizing study characteristics, outcomes, and effect sizes are valuable but require clearer organization and synthesis of findings.

Comments and Recommendations:

1. The abstract concisely summarizes the study but should provide a clearer statement on the key limitations and future directions.
2. The background on PRS and PGx is well articulated, but a brief mention of major PRS scoring methodologies would be beneficial.
3. While the methodology is sound, a clearer explanation of how PRS were evaluated across studies would improve the reader’s understanding.
4. The manuscript provides detailed tables, but the narrative synthesis should highlight trends more explicitly rather than listing study findings sequentially.
5. Emphasize the translational gap between PRS research and clinical implementation.
6. Address the impact of PRS on clinical guidelines and personalized treatment algorithms.
7. Discuss potential ethical concerns associated with genetic stratification in pharmacogenomics.
8. The conclusion effectively summarizes the findings but should include a stronger statement on the next steps for research and clinical adoption.

This manuscript provides an insightful and timely review of PRS in cardiovascular pharmacogenomics. While it effectively presents the current landscape, several areas require further development, particularly in meta-analysis, cost-effectiveness considerations, and practical implementation challenges. Addressing these issues will enhance the manuscript’s impact and relevance to both researchers and clinicians.

Moderate revisions are required before acceptance.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript makes a solid contribution by mapping the current landscape of PRS in cardiovascular pharmacogenomics. Its structured approach and critical discussion offer helpful insights for clinicians and researchers interested in the future of precision medicine in cardiovascular care.
The authors rightly point out the issue of genetic diversity in PRS studies; however, they should suggest some practical solutions for increasing inclusivity in genetic research.
To improve clarity and readability, the authors must consider expanding the tables' captions to explain key terms used in each column: for example, the term 'Validation/Test dataset' is not explicitly defined in Tables 2--7. (It would be helpful to specify whether this refers to an independent cohort used for external validation, a subset of the discovery dataset, or a replication dataset.)

Author Response

Please see the attachment.

Author Response File: Author Response.pdf