Dear Dr.  Yatagai,

Thank you for your email and for the opportunity to revise and resubmit our manuscript titled "Impact of hereditary predisposition to increased BMI on adult asthma phenotype". We appreciate the time and effort the reviewers and editorial team have taken to evaluate our work.

Please submit your revised manuscript by Sep 21 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Salman Bashir, M.S.C

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1.Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager.

3. We note that your Data Availability Statement is currently as follows:

“All relevant data are within the manuscript and its Supporting Information files.”

Please confirm at this time whether or not your submission contains all raw data required to replicate the results of your study. Authors must share the “minimal data set” for their submission. PLOS defines the minimal data set to consist of the data required to replicate all study findings reported in the article, as well as related metadata and methods (https://journals.plos.org/plosone/s/data-availability#loc-minimal-data-set-definition).

For example, authors should submit the following data:

- The values behind the means, standard deviations and other measures reported;

- The values used to build graphs;

- The points extracted from images for analysis.

Authors do not need to submit their entire data set if only a portion of the data was used in the reported study.

If your submission does not contain these data, please either upload them as Supporting Information files or deposit them to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories.

If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. If data are owned by a third party, please indicate how others may request data access.

4. Please amend either the abstract on the online submission form (via Edit Submission) or the abstract in the manuscript so that they are identical.

5. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Additional Editor Comments:

We are encouraged by your assessment that the manuscript has merit and are grateful for the constructive feedback provided. In response, we have carefully revised the manuscript to address all the comments and concerns raised during the review process. We believe these revisions have significantly improved the clarity, rigor, and overall quality of the manuscript.

• Indicate which changes you require for acceptance versus which changes you recommend
• Address any conflicts between the reviews so that it's clear which advice the authors should follow
• Provide specific feedback from your evaluation of the manuscript

publication criteria  and not, for example, on novelty or perceived impact.

[Note: HTML markup is below. Please do not edit.]

Comments to the Author

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

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: Yes

Reviewer #4: I Don't Know

**********

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

The PLOS Data policy

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

Reviewer #1: Line 35 isn't justified based on the finding - suggest remove 'asthma may contribute to increased BMI.'

Comparison should have been made between asthma vs overweight asthma and overweight vs overweight asthma.

Why 2 different cohorts?

Why were different SNP genotyping methods used?

Incomplete summary for rs939584 in table.

Duplication of SNP selection and BMI-GRS score in methods and results.

Line 206-212 should be in discussion

Table 2 - Mann Whitney spelling error. Was there a weighted difference in BMI due to the difference in number of healthy and asthmatic participants for a difference of 0.52 to be significant?

A graph showing no correlation between BMIGRS and asthma should be included

Reviewer #2: This is a comprehensive and interesting study about the association between adult onset asthma and BMI, in a large cohort of subjects. A minör point to critise is the mean BMI of patients and healthy controls is not matched! It is better to analyse at least a subgroup of controls with a matched BMI with the asthmatics.

Reviewer #3: The study aimed to investigate the role of genetic predisposition to increased BMI, evaluated by calculating a BMI-genetic risk score (BMI-GRS), on adult asthma phenotypes and explore whether these genetic factors might distinguish certain subgroups of overweight or obese asthma patients. The study included 1530 healthy individuals and 735 adult asthma patients. Six single nucleotide polymorphisms (SNPs) which were confirmed as having an association with BMI in the healthy population in the study were used to calculate BMI-GRS. The authors found that patients with asthma had significantly higher BMI values compared to non-asthmatic healthy controls, but there was no significant difference in BMI-GRS between the two groups. The study reported that no significant correlation was found between BMI and BMI-genetic risk scores in asthmatic patients. The authors performed a cluster analysis using age of asthma onset, %FEV1, BMI and BMI-GRS. This analysis identified 6 distinct asthma patient groups, among these, two clusters were characterized by increased BMI, one with a higher BMI-GRS and the other with a lower BMI-GRS. I have some major and minor comments.

- Lines 174-178, the population attributable risk fraction (PARF) was calculated assuming there are no confounding factors, and no confounding adjustment in the calculation of PARF was performed. Additionally, PARF assumes that a cause-effect relationship exists between the exposure and outcome. However, the study reported that there was no significant correlation between BMI and BMI-genetic risk scores in asthmatic patients. This is a limitation.

- Abbreviations should be added to Table 1. In table 1 the summary part of rs939584 is not completed.

- Lines 187-199 of the results section is about methods.

- Line 197, table 1a, 1b, there is no table 1a or 1b.

- Lines 206-212 of results section would be more appropriate in discussion.

- I suggest adding more clinical characteristics on table 2, like BMI groups, obesity and overweight rates.

- I suggest adding the criteria defining atopy to the methods section.

- Lines 229-235 of the results section is about methods.

- The authors stated in lines 268-270 that ‘Our results suggest that genetic factors influencing BMI may play a crucial role in the development of adult-onset overweight/obese asthma in certain patients, particularly those in Cluster-5, where a higher BMI-genetic risk score (BMI-GRS) was observed.’. For this comment multivariate analyses should be performed. Additionally, no significant correlation was found between BMI and BMI-genetic risk scores in asthmatic patients in the study.

- Lines 276-285, If clinical features are not different among the two phenotypes (cluster 5 and 6), what is the added value of BMI-GRS calculation? I suggest discussing this.

- I suggest adding clinical comparison of all 6 clusters to the results section.

- In lines 294-296, it is stated that ‘Specifically, asthma symptoms may lead to weight gain in some patients due to reduced physical activity or medication side effects, while genetic predispositions to obesity may increase the risk of developing asthma in others.’. I suggest adding previous literature data and a detailed discussion.

- In lines 297-299, it is stated that ‘In conclusion, this study supports the growing body of evidence suggesting that genetic susceptibility to higher BMI is a key factor in the development of adult-onset asthma in certain subgroups of overweight or obese patients.’. As the study does not include a multifactorial analysis and a longitudinal analysis, I suggest to revise the conclusion part to be supported by the data.

- The discussion section of the manuscript includes only one reference. The discussion section needs a revision and expansion to discuss the results with other previous studies.

- I suggest giving percentages in the x axes of figure 4.

Reviewer #4: I read with interest the manuscript entitled “Impact of hereditary predisposition to increased BMI on adult asthma phenotype”. The manuscript describes the results of a study delving into the genetic susceptibility to elevated body mass index (BMI) and its subsequent influence on adult-onset asthma, specifically within a Japanese cohort. This study indicates a bidirectional relationship: genetic predisposition to a higher BMI appears to contribute to adult-onset overweight/obese asthma, and conversely, asthma itself may lead to increased BMI. Therefore, the study provides valuable results that contribute to progress in the fields of precision medicine and precision nutrition.

The manuscript is generally well-written. Nevertheless, some aspects of the manuscript should be addressed before a decision on publication. The manuscript needs revision focused on the remarks stated below.

MAJOR REMARKS:

• Title: Please consider reformulating the title so that it is understood that the study was conducted in Japan. This suggestion is made in the context that the Japanese population has particularities regarding being classified as overweight/obese in relation to BMI.

• Line 42: Please provide recent data regarding the prevalence of both obesity and asthma, at global level and in Japan, respectively.

• Line 45: Please define BMI.

• Lines 45-49: The mechanisms by which obesity contributes to the pathogenesis of asthma need to be described more extensively, citing a significantly larger number of scientific publications. For instance, potential mediators between obesity and asthma should be briefly described (e.g., mechanical changes, systemic inflammation, sex hormones, arginine metabolism, gut microbiome) (https://pmc.ncbi.nlm.nih.gov/articles/PMC9671155/#S3; https://www.sciencedirect.com/science/article/pii/S1323893023000837?via%3Dihub#sec3). Asthma phenotypes in obesity (e.g., Late-Onset Asthma

Phenotype, Early-Onset Asthma

Phenotype) should also be mentioned (https://pmc.ncbi.nlm.nih.gov/articles/PMC11204497/#sec5-jcm-13-03474).

• Discussion section: this section must be thoroughly revised. Discussions must be based on scientific articles already published on the topic of the study. Currently, only one scientific article is cited in the discussion section, and this aspect needs to be significantly improved.

MINOR REMARKS:

• Line 92: Please provide the date of issue of the ethical approval number.

• Table 1: The references in the table should be moved to the reference list and kept in the table only as numbers.

• Figure 5: Please remove the text “Figure 1” from this figure.

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step.

Attachments

Attachment

Submitted filename: Review report.docx

Genetic predisposition to elevated BMI and adult asthma phenotypes in a Japanese population

PONE-D-25-02383R1

Dear Dr. Yatagai,

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.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager®  and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support .

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Muhammad Salman Bashir, M.S.C

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

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

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: I Don't Know

Reviewer #3: Yes

**********

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

The PLOS Data policy

Reviewer #2: Yes

Reviewer #3: (No Response)

**********

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

Reviewer #2: Yes

Reviewer #3: (No Response)

**********

Reviewer #2: This is a Great work , as well as a comprehensive and interesting study about the association between adult onset asthma and BMI, in a large cohort of subjects. Our minör point was the mean BMI of healthy controls was not matched to patient group! The authors replied that they conducted BMI-adjusted models to estimate the direct effects of the BMI-GRS by comparing non-asthmatic healthy controls with patients with asthma. This analysis also confirmed that asthma is not associated with the BMI-GRS, even when adjusted for BMI (p = 0.87), and was mentioned in the result section of the revised manuscript

Reviewer #3: All of the comments and criticisms of the reviewers have been carefully and fully addressed. The study showed that BMI-associated genetic variants showed differential distribution patterns across six distinct asthma clusters, with elevated BMI-GRS observed in both obese and non-obese phenotypes. The manuscript is well written.

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #2: No

Reviewer #3: No

**********