Identifying genetic variants associated with ritodrine-induced pulmonary edema

Seung Mi Lee; Yoomi Park; Young Ju Kim; Han-Sung Hwang; Heewon Seo; Byung-Joo Min; Kye Hwa Lee; So Yeon Kim; Young Mi Jung; Suehyun Lee; Chan-Wook Park; Ju Han Kim; Joong Shin Park

doi:10.1371/journal.pone.0241215

Peer Review History

Original SubmissionJuly 24, 2020
27 Aug 2020 Decision Letter - Frank T. Spradley, Editor PONE-D-20-22975 Identifying genetic variants associated with ritodrine-induced pulmonary edema PLOS ONE Dear Dr. Kim, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. An expert in the field handled your manuscript, we are very thankful for their time and efforts. Although interest was found in your study, some concerns arose during review that overshadowed this enthusiasm. Notably, the authors need to expand on what their findings about these select genes mean in regards to pulmonary edema and there are questions about the data analysis. Please respond to ALL of the reviewer's comments in your revised manuscript. Please submit your revised manuscript by Oct 11 2020 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'. 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Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: No ****** 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: 1: The author and research team provide another aspect of genetic variants, distinguishing from their previous publication in year 2018 (title: Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects ). In this submitting paper, the authors empathize particular two gene variants (CPT2 & ADRA1A), an interesting question emerged that how ciliapathy related genes or CPT2 & ADRA1A really functions or impact during ritodrine-induced pulmonary edema. Authors could elaborate it or provide more insights within this article. 2: From the results the authors reveal that (CPT2 rs2229291, GG) , (CPT2 rs2229291, TG) and ADRA1A (rs2229126, TA) are significant to ritodrine-induced pulmonary edema. In discussion, authors try to interpret these clinical observations could be causative to the adverse effect in terms of basic studies (such as β2-knockout mouse and CPT2-deficient mouse models). How influential to these genetic variants it will be and any other previous cell-based studies mentioned the function of these genetic variants in different experimental settings. 3: Certain statistics and linguistic could be fortified and precise. ****** 6. PLOS authors have the option to publish the peer review history of their article (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: Yes:** Dr. Heng-Liang Lin [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. https://doi.org/10.1371/journal.pone.0241215.r001
Revision 1
12 Sep 2020 Author Response ## Dear Editor: Thank you very much for the additional comments and suggestions. We have modified the manuscript according to the comments below. 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 RESPONSE ==> We formatted our manuscript according to the appropriate style manual. 2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) 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. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. RESPONSE ==> We had uploaded our study’s minimal underlying data set as Supporting Information file (S3 Table). 3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information RESPONSE ==> We included captions for our Supporting Information files at the end of our manuscript. 4. Your ethics statement must appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please also ensure that your ethics statement is included in your manuscript, as the ethics section of your online submission will not be published alongside your manuscript. RESPONSE ==> We added ethics statement in the Methods section. We hope this is sufficient for the manuscript to be accepted for publication in PLOS ONE. On behalf of all the co-authors Yours sincerely Ju Han Kim ##Dear Reviewer: We greatly appreciate the valuable comments, which have helped to improve the quality of our manuscript. We are hereby submitting a version of the manuscript that has been revised in accordance with your comments. Our point-by-point responses to your comments appear below. Q1. The author and research team provide another aspect of genetic variants, distinguishing from their previous publication in year 2018 (title: Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects). In this submitting paper, the authors empathize particular two gene variants (CPT2 & ADRA1A), an interesting question emerged that how ciliapathy related genes or CPT2 & ADRA1A really functions or impact during ritodrine-induced pulmonary edema. Authors could elaborate it or provide more insights within this article. RESPONSE ==> We sincerely thank the reviewer for this valuable comment. Our previous study (Seo et al.) reported ciliary-related genes as candidates for ritodrine-induced side effects in a group that included patients with mild to severe cardiac and pulmonary dysfunction such as pulmonary edema, dyspnea, tachycardia, and palpitations. In this study, we narrowed our focus to patients with ritodrine-induced pulmonary edema (extreme cases) and identified two particular candidate genes associated with this side effect using matched controls. Contrary to the previous result, the two identified genes are not classified as ciliated-related genes and are still expected to be associated with ritodrine-induced adverse reactions, especially pulmonary edema. In the discussion, we attempted to explain how CPT2 and ADRA1A may contribute to the pathogenesis of pulmonary edema, but further research is needed to evaluate how these genes actually affect the action of ritodrine. We have added the limitation of the present study to the discussion. [Correction in the revised manuscript] (In the Discussion, 6th paragraph) … the current study. Future directions should focus on appropriate experimental evaluation of how candidate variants affect the pharmacokinetics of ritodrine and pulmonary edema. Q2. From the results the authors reveal that (CPT2 rs2229291, GG) , (CPT2 rs2229291, TG) and ADRA1A (rs2229126, TA) are significant to ritodrine-induced pulmonary edema. In discussion, authors try to interpret these clinical observations could be causative to the adverse effect in terms of basic studies (such as β2-knockout mouse and CPT2-deficient mouse models). How influential to these genetic variants it will be and any other previous cell-based studies mentioned the function of these genetic variants in different experimental settings. RESPONSE ==> In previous studies, CPT2 rs2229291 has been known to exhibit reduced enzymatic activity under high fever. Yao et al.’s study showed that COS-7 cells transfected with a compound variant including rs2229291 exhibited decreased fatty acid b-oxidation, intracellular ATP levels, and mitochondrial membrane potential, which results in mitochondrial fatty acid metabolism disruption and brain edema in patients with influenza-associated encephalopathy. No previous cell-based studies were found for ADRA1A rs2229126. How these variants modulate variability in drug actions should be further evaluated in future studies. We have added the limitation of the present study to the discussion. [Correction in the revised manuscript] (In the Discussion, 5th paragraph) …in lung tissue. There has been a report of decreased activity of CPT2 with rs2229291 in hyperthermic conditions, resulting in impaired fatty acid oxidation and a mitochondrial energy crisis in vascular endothelial cells [34]; however, the direct functional impact of the variant on ritodrine-induced pulmonary edema should be further evaluated in future studies. Q3. Certain statistics and linguistic could be fortified and precise. RESPONSE ==> We thank the reviewer for this helpful comment. As suggested by the reviewer, a multivariate logistic regression was performed that adjusted for the cesarean delivery effect, where the p-value was less than .1 (p = 0.077) between groups (Supplementary Table S2). Even after adjustment, the p-value of CPT2 rs2229291 remained statistically significant (p = 0.048), whereas ADRA1A rs2229126 did not reach statistical significance. However, no formal adjustments were required, as there were no significant differences between groups in clinical features. We've also edited grammar, punctuation, and sentence structure to improve clarity. The comment is reflected on in the revised manuscript. [Correction in the revised manuscript] (In the Results, Candidate variant prioritization and validation part) had a marginal association signal (OR = Inf (1.0-Inf), Fisher’s exact test p-value = 0.053)… CPT2 rs2229291 remained statistically significant even after adjustment for the cesarean delivery effect (multiple linear regression p-value = 0.048, S2 Table). Attachments Attachment Submitted filename: Ritodrine_Response_to_reviewers.docx https://doi.org/10.1371/journal.pone.0241215.r002
12 Oct 2020 Decision Letter - Frank T. Spradley, Editor Identifying genetic variants associated with ritodrine-induced pulmonary edema PONE-D-20-22975R1 Dear Dr. Kim, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. 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, Frank T. Spradley Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0241215.r003
Formally Accepted
29 Oct 2020 Acceptance Letter - Frank T. Spradley, Editor PONE-D-20-22975R1 Identifying genetic variants associated with ritodrine-induced pulmonary edema Dear Dr. Kim: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Frank T. Spradley Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0241215.r004

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