Molecular-Genetic Basis of Pulmonary Arterial Hypertension (PAH)

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript provides a detailed overview and interpretation of the genes underlying pulmonary arterial hypertension, as well as modern methodological approaches that have expanded understanding of the genetic architecture of the disease beyond individual genes. The topic is current and scientifically relevant. However, despite its comprehensiveness, the review is more descriptive than critical overall, with limited discussion of the advantages and limitations of the approaches presented, as well as their interrelationships. In addition, the formal aspects of the manuscript do not align with the journal's guidelines, particularly regarding text structure, specification of key words, and reference formatting, and require appropriate corrections.

1. The manuscript is not structured according to the journal's requirements. Sections and subsections are not numbered, which makes it somewhat difficult to follow the structure of the manuscript. It would be beneficial to introduce numbering, which would contribute to better clarity and easier navigation in the text.
2. Key words are not listed in the manuscript, so it would be important to add them for better indexing and searchability.
3. The contribution of technologies is well described, but lacks sufficient critical analysis. It would be helpful to broaden the discussion to include their advantages and limitations, as well as their interrelationships and complementarities.
4. The authors could consider adding another illustrative Figure to show the role of new technologies in PAH research, particularly their interrelationship and contribution to understanding the relationship between genotype and phenotype.
5. Given that the review deals in detail with genes currently implicated in PAH pathogenesis and new technological approaches, it would be beneficial to consider introducing an additional section that would more explicitly link these two aspects that this review focuses on most.
6. The data presented in Table 1 are scientifically relevant, but the interpretation of some appears simplistic and incomplete.
7. The data presented in the Table 2 are mostly relevant, however, certain inconsistencies and inaccuracies were observed that require correction. Some descriptions of gene function are incomplete (BMPR2: "These in turn activate the ...", SMAD1: "This gene encodes SMAD1, which ..."; GGCX: "crucial in regulating ..."...) or terminologically imprecise (TBX4: "This gene encodes the fibroblast growth factor 10...", as a transcription factor, TBX4 binds to the promoter region of the FGF10 gene, directly regulating its expression), while for some genes with a limited level of evidence, the formulations are too categorical. Also, minor errors in the labeling of protein products and inconsistencies in the way of citing references were observed. A careful revision of the table is recommended in order to improve the accuracy, clarity and consistency of the data presented.
8. The citation style and the reference list are not consistent with the journal’s guidelines and should be revised accordingly. Also, neither the Author Contributions nor the Data Availability Statement are listed.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

The article “MOLECULAR-GENETIC BASIS OF PULMONARY ARTERIAL HYPERTENSION (PAH)” represents the molecular genetic basis of the development of hypertension. Such a genomic-proteomic approach to the pathogenesis of PAH (pulmonary arterial hypertension) is very relevant and modern. The genes involved in the pathogenesis are presented. This could serve as a basis for gene therapy of this disease, especially if SNPs are present. In this regard, it is highly desirable to supplement the article with data on polymorphisms in these genes, as well as on which pharmacogenetic tests are already being used or could be recommended for use to personalize PAH therapy.

1. It is desirable to add the SNPs
2. Line 1663-1665: incorrect sentence
3. Nothing is written about smoking and atherosclerosis
4. GWAS has not been abbreviated

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript provides a broad narrative overview of the molecular and genetic processes underlying pulmonary arterial hypertension (PAH), covering 30 genes and their functional categories. However, several key elements are missing and must be included for the review to meet the standards required for a rigorous, methodologically transparent scientific article:

1) The manuscript does not describe the literature search strategy, including the databases used, the time frame, the keywords and the inclusion/exclusion criteria. Without this information, the review remains purely descriptive and its completeness cannot be evaluated. A dedicated Methods section is required to ensure transparency and reproducibility.

2) Several key assertions regarding penetrance, 'second-hit' factors, functional gene categories, the prevalence of BMPR2 mutations and the convergence of disease-related pathways are presented without supporting references. Given the depth of biological interpretation, all such statements must be accompanied by primary or high-quality secondary sources.

3) Interpretations of disease-related processes are often presented as established facts, even for genes supported by limited or preliminary data. The review would benefit from clearer differentiation between well-validated findings, emerging hypotheses and results based on small cohorts or model systems. A more explicit evaluation of evidence quality is needed.

4) While the genetic and molecular landscape is described in depth, the manuscript provides minimal discussion of how these insights inform clinical practice, including diagnostics, risk stratification, therapeutic decision-making and genotype-guided interventions. Expanding the translational context would substantially enhance the review’s relevance.

For these reasons, I recommend Major Revision.

 

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have carefully considered the reviewers’ comments and have significantly improved the manuscript. The revised version includes a clearer discussion of the advantages, limitations, and complementarities of the various genomic, transcriptomic, epigenomic, and multiomic approaches considered in the review. The additional sections and expanded discussion enhance the overall structure and relevance of the manuscript.

The integration of PAH-related genes with emerging technologies, methodological limitations, unresolved issues, and clinical implications are further discussed, contributing to a more balanced review of the field.

Overall, the authors have taken the reviewers’ comments seriously and made changes that have significantly improved the quality and readability of the review. Although some sections remain somewhat descriptive, the manuscript represents a substantial improvement over the original submission.

Author Response

Thank you for the feedback. I added critical analysis to the parts that seemed somewhat descriptive.

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for the clear answers and corrections. The article has been improved, and the pharmacogenetic aspects have been addressed

Author Response

Thank you for your constructive feedback.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Editor,

Please could you clarify how Figure 4 was generated? This should include information on whether it was created by the authors, and details of the databases, software tools or graphical resources used. This information would improve the transparency of the review.

Additionally, Table 1 requires a stylistic revision, since nearly every entry begins with the phrase 'This gene encodes...'. I recommend varying the sentence structure to avoid repetition and enhance readability.

 

Author Response

Please see the attachment

Author Response File: Author Response.pdf