-->PONE-D-25-68169-->-->Genetic Predisposition to High Blood Pressure and Out-of-Office Hypertension: Insights from a Population Sample in Liechtenstein-->-->PLOS One

Dear Dr. Narula,-->-->

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Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

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-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: Manuscript # PONE-D-25-68169

In this study entitled “Genetic Predisposition to High Blood Pressure and Out-of-Office Hypertension: Insights from a Population Sample in Liechtenstein”

the authors evaluated the family history and polygenic risk scores (PRS) to measure the predisposition to hypertension. According to the results PRS provides incremental information in identification of individuals with ambulatory hypertension, unlike family history.

Comments:

Having parents, siblings, or grandparents (especially early-onset) with high blood pressure increases your own likelihood. Having one or more close family members with high blood pressure before age 60 doubles your risk. It is not solely genetic; shared family behaviors (diet, lifestyle) and genetic predisposition both play a role (Eur Heart J. 2017;38(29):2300–2308; Front. Pediatr 2018. 5:285; Nature Genetics 2019;51:51–62).

- Data regarding family history of hypertension should be collected in a detailed and accurate manner. In this study, the family history of hypertension was only reported. In this context, it is important to know the parents' age, because depending on the parents' age, blood pressure levels may not have met the criteria for hypertension according to current guidelines.

- A reported family history (FH) of hypertension may result in lower sensitivity of FH as an incremental predictor of ambulatory hypertension. Furthermore, parental age may be a confounding factor regarding this issue.

- In the conclusion of the study authors suggested “the possibility of PRS having clinical utility in future applications as methodology improves.” Considering that: "PRS provides modest incremental information in determining hypertension status outside the office in young, healthy individuals," do the authors believe that the cost-benefit ratio will be worthwhile for using the method in the clinic?

Reviewer #2: The manuscript evaluates two measures of genetic predisposition to hypertension—family history and polygenic risk scores (PRS)—and examines their association with blood pressure traits using a validated prediction model. The authors further assess the incremental predictive value of these measures.

The study population appears well-characterized and representative. The findings may be relevant for the development of predictive models aimed at identifying individuals at increased risk of daytime ambulatory hypertension using readily available clinical and genetic information. However, the relatively limited clinical utility reported should be carefully considered.

The following comments and suggestions are intended to improve the scientific quality, clarity, and presentation of the manuscript.

Major Comments

1. Cohort Selection and Clinical Interpretation

The GAPP cohort began recruitment approximately 16 years ago. The authors should clarify the rationale for restricting the study population to individuals aged 31–40 years. Additionally, if participants were healthy at baseline, the implications of detecting hypertension (both office-based and ambulatory) during follow-up should be discussed in greater depth, particularly in terms of clinical relevance and potential early risk stratification.

2. Genotyping Methodology and Data Transparency

The manuscript lacks sufficient detail regarding the genotyping results obtained using the HumanCoreExome BeadChip. The authors should:

o Specify the number of unrelated individuals included in the genetic analyses.

o Report the total number of genetic markers analyzed and those excluded after quality control.

o Clarify how these data contributed to PRS construction.

Including this information would enhance reproducibility and methodological transparency.

3. Interpretation of Predictive Models

In Table 3, the inclusion of additional model performance metrics—such as the change in Akaike Information Criterion (ΔAIC)—is recommended to facilitate interpretation of the incremental value of PRS and family history. This would strengthen the evaluation of model improvement.

Moderate Comments

4. Clarification of Statistical Measures

In Table 2, it should be clearly stated whether the reported β coefficients represent changes in mmHg per standard deviation (SD) increase in the predictor variables.

5. Completeness of Tables and Footnotes

o Tables 3 and 4: The term “Proof BP RC” appears to be missing or incomplete and should be corrected.

o Table 4: Abbreviations such as RL, Sen, and Spec should be explicitly defined in the footnote.

o Table 2: The sample size (n) should be included for both PRS and family history analyses.

6. Organization of Supplementary Material

The placement and referencing of supplementary material within the main text should be improved to ensure a logical and coherent flow of information.

Minor Comments

7. Tables and Formatting

o Table 1 should explicitly indicate whether values are presented as mean ± standard deviation or in another format.

o Numerical ranges should be consistently formatted using hyphens (e.g., 10–20) rather than commas throughout the text and tables.

o Abbreviations should be standardized (e.g., use “FHx” consistently instead of “Fam Hx” in Tables 3 and 4).

8. Abstract and Keywords

The relevance and specificity of the keywords should be reviewed to ensure they accurately reflect the main topics and improve indexing.

9. Citations and References

Additional citations should be incorporated where appropriate to support statements and contextualize findings within the existing literature. Attention should also be paid to correct punctuation placement (e.g., periods after parentheses in in-text citations).

10. Language and Typographical Errors

The manuscript requires careful proofreading to correct typographical errors and ensure consistency in language usage throughout.

Overall, the manuscript addresses a relevant topic in cardiovascular risk prediction. Addressing the points outlined above will substantially improve its clarity, methodological rigor, and interpretability.

Reviewer #3: The study aimed to investigate whether genetic predisposition can identify individuals with ambulatory daytime hypertension by analyzing family history and polygenic risk scores (PRS) in a White European sample from Liechtenstein. The authors conclude that PRS provides incremental value in identifying individuals with ambulatory hypertension, whereas family history does not. However, these improvements are modest and highlight the need for further refinement to enhance predictive utility in clinical practice.

General Comment

I agree with the authors that PRS offers only a modest improvement and that further research is warranted to enhance its predictive value at the point of care. Overall, the manuscript is well written, and the study appears to be carefully conducted.

General Question

Based on their experience, do the authors foresee a role for PRS testing in future clinical practice for hypertension, particularly in the context of both ambulatory and office-based hypertension?

Specific Questions for the Authors

How was family history of hypertension assessed? While this is often considered a simple binary variable (yes/no), it is not always accurately known. How reliable do the authors consider this commonly used measure?

Do the authors believe it would be useful to collect more detailed information, such as the age at onset of hypertension in relatives or whether (and which) relatives were receiving antihypertensive treatment?

Family history is an important risk factor, particularly when focused on first-degree relatives. Does the predictive value differ depending on whether the affected relatives are parents, siblings, or offspring?

Would it be informative, for example, to investigate hypertension during pregnancy in female relatives? More broadly, does stratifying family history by sex (e.g., mother vs. father, sisters vs. brothers) add meaningful information?

The study population is relatively young; therefore, a hypertension prevalence of 12% is noteworthy. Could stress—or any available measures of stress—have influenced the observed blood pressure values?

Was any correlation observed between blood pressure and heart rate? Including this information might provide additional insight.

Among participants identified as hypertensive, how many were already aware of their condition?

Were comorbidities (beyond common risk factors) taken into account in the data collection and analysis?

The inclusion and exclusion criteria are referenced (ref. 11), but a brief summary in the manuscript would improve readability.

The HumanCore Exome BeadChip by Illumina is mentioned: is this a validated tool? It would be helpful to include an appropriate reference.

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Reviewer #1: Yes: Heno Ferreira Lopes

Reviewer #2: Yes: Maria Cristina Moran Moguel

Reviewer #3: No

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Genetic Predisposition to High Blood Pressure and Out-of-Office Hypertension: Insights from a Population Sample in Liechtenstein

PONE-D-25-68169R1

Dear Dr. Narula,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Marcelo Arruda Nakazone, M.D., Ph.D.

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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-->2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Yes

Reviewer #2: Yes

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-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: Yes

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-->4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

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-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: Yes

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-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: Manudcript#PONE-D-25-68169R1

Comments:

- The authors did not address every question precisely. Since a database is involved, I imagine that some data may not be available.

- The results obtained add little to clinical application at this time.

- In light of the responses to all reviewers, there has been significant improvement in the writing and presentation of the results. The study opens up prospects for future research aimed at better identifying the potential genetic polymorphisms involved in the pathogenesis of hypertension.

Reviewer #2: The authors have responded promptly and satisfactorily to all my comments and observations. The modifications made and the considerations added, primarily in the discussion section, are relevant and have clarified the study.

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Reviewer #1: No

Reviewer #2: No

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