Association between dyslipidemia and the risk of incident chronic kidney disease affected by genetic susceptibility: Polygenic risk score analysis

Boram Weon; Yunjeong Jang; Jinyeon Jo; Wencheng Jin; Seounguk Ha; Ara Ko; Yun Kyu Oh; Chun Soo Lim; Jung Pyo Lee; Sungho Won; Jeonghwan Lee

doi:10.1371/journal.pone.0299605

Peer Review History

Original SubmissionAugust 13, 2023
9 Oct 2023 Decision Letter - Marcelo Arruda Nakazone, Editor PONE-D-23-23585Association between dyslipidemia and the risk of incident chronic kidney disease affected by genetic susceptibility: polygenic risk score analysisPLOS ONE Dear Dr. Lee, 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. ============================== ACADEMIC EDITOR: The manuscript is interesting but will require further reworking and a major revision.<o:p></o:p> While they recognize the potential interest of the subject studied, the reviewers raised a number of important issues that need to be properly addressed. ============================== Please submit your revised manuscript by Nov 23 2023 11:59PM. 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Please remove them and upload them with the file type 'Supporting Information'. Please ensure that each Supporting Information file has a legend listed in the manuscript after the references list. 4. 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. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. 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: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. 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 ****** 4. 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 ****** 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: The manuscript titled "Association between dyslipidemia and the risk of incident chronic kidney disease affected by genetic susceptibility: polygenic risk score analysis" delves into the intricate relationship between dyslipidemia, genetic predisposition (quantified using a polygenic risk score, or PRS), and the onset of chronic kidney disease (CKD). Drawing data from the extensive UK Biobank cohort, the study meticulously constructs a PRS to encapsulate individual genetic susceptibility. Through multivariable Cox regression models, the authors unveiled that heightened triglyceride levels and diminished levels of total cholesterol, LDL-C, and HDL-C amplify the risk of CKD. Moreover, the PRS emerged as a potent predictor of CKD, with a notable interaction between triglyceride levels and PRS, especially in the low-PRS group, signifying a heightened CKD risk. This research bridges genetic markers and phenotypic indicators to shed light on CKD risk. The methodological rigor, combined with the vastness of the dataset, instills confidence in the findings. However, while the core analysis is robust, the manuscript could benefit from a deeper exploration of underlying mechanisms and broader implications, ensuring the results resonate more profoundly within clinical and research landscapes. 1 - The introduction effectively provides a broad context of the topic at hand. However, the inconsistencies related to dyslipidemia's impact on renal function could be more clearly elucidated. Additionally, delving deeper into the clinical implications, particularly those concerning statin interventions, would enrich the discussion. To enhance the scientific rigor of the introduction, it's essential to emphasize the study's significance, highlight gaps in the existing literature, and clearly outline the foundational rationale behind the research. 2 - Considering the comprehensive methodology you outlined for PRS construction, how did the LDpred2 algorithm's performance compare to the other four algorithms in terms of specificity, sensitivity, and overall accuracy? Could you provide a table or figure that visually contrasts the performance metrics of each algorithm, and elaborate on the primary factors that led to the selection of LDpred2 as the optimal PRS model over the others? 3 - How might the exclusions, particularly those concerning ethnicity and relatedness, affect the broader applicability of the study's findings to diverse populations? Considering the exclusions based on non-white ethnicity and relatedness up to the 3rd degree, have you considered conducting a Principal Component Analysis (PCA) to illustrate the ancestral background of both the included and excluded participants? Such an analysis could provide insights into the genetic diversity of the cohort and further contextualize the potential generalizability of your findings. 4 - Your study unveils the potential of PRS in capturing the risk of incident kidney diseases and emphasizes its interaction with lipid levels, particularly triglycerides. Given this novel insight, are there plans to further investigate the specific genetic loci or pathways that might be mediating this interaction? 5 - Would it be possible to produce a Manhattan plot that illustrates the risk alleles (SNPs) linked to incident CKD within the UK Biobank cohort? 6 - Given that the UK Biobank's population is predominantly white, how imperative is it to replicate this study across diverse ethnic groups to validate the universal applicability of your findings? Reviewer #2: This is an interesting study that evaluated the association between lipid levels, polygenic risk score and incident CKD in a large population. The authors found that high triglyceride was associated with incident CKD in the low-PRS group. This association was significant after adjustment to diabetes and statin use, but the model was not adjusted to fibrate use. This is the main limitation of the study knowing that fibrate use for hypertrigyceridemia can induce an increase in serum creatinine. Could this confounding variable be added to the regression model? ****** 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: No Reviewer #2: 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". 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Revision 1
3 Dec 2023 Author Response We thank the reviewers for the insightful comments and valuable suggestions. We have revised the manuscript accordingly after the first decision of major revision. Our response to the comments from the reviewers is as follows, and for detailed information, please refer to the attached 'Rebuttal letter.docx.'. Reviewer #1: #1-1 Thank you for the important comment. Following the valuable comments from the reviewer, we have added additional descriptions in the Introduction section to emphasize the significance of the present study based on inconsistencies in the existing literature. #1-2 : Thank you for the valuable comment. Following the comment, we present a comparison of each PRS algorithm for selecting optimal PRS as a supplemental table. We utilized five different algorithms: P+T, C+T, LDpred2, LASSOsum, and PRScs, to calculate the PRS. Specifically, for LDpred2 PRS, we employed a grid model (LDpred2_grid) with proportions of causal variants set at 0.03, 0.01, 0.3, 0.1, and 1, and also utilized an infinitesimal model (LDpred2_inf) and an auto model (LDpred2_auto). Supplemental Table 1 (S1 table) visualizes the performance comparison for each PRS. After careful evaluation, we have selected LDpred2_grid_0.03 as the optimal PRS, which demonstrated the highest correlation (R=0.061), significance (p=1.18E-43), and the lowest Akaike information criterion (AIC = 25199.84). In the Method section, we added the description explaining this process. #1-3 Thank you for your valuable suggestion. The primary objective of our manuscript is to explore the impact of genetic factors on the relationship between dyslipidemia and chronic kidney disease (CKD) risk, using polygenic risk scores (PRS) in a European population. We utilized the UK Biobank data, which encompasses a large number of subjects, and therefore chose to focus exclusively on the European population to enhance the robustness of our analyses. Additionally, in light of your comment, we reviewed the multidimensional scaling (MDS) plot and concluded that focusing on the European population is indeed the most suitable approach for our study. #1-4 Thank you for the insightful comment. The reviewer highlighted the necessity of investigating specific risk loci or pathways involved in the interaction between dyslipidemia and genetic risk for CKD. While the reviewer’s suggestion is indeed important, it is considered that an extensive analysis in this direction would require resources beyond the current scope of our research. However, recognizing the significance of this intriguing topic, further investigation is deemed necessary to elucidate and expand upon it. We added the descriptions that explains the rationale behind these needs. #1-5 Thank you for your valuable comment. The primary objective of our research is to examine the interaction between genetic factors for CKD, manifested by PRS, and the influence of dyslipidemia on CKD. Manhattan plots for CKD risk alleles have already been presented in several GWAS utilizing various cohorts. Consequently, we acknowledge that providing additional Manhattan plots in our study may have a relatively lower impact in terms of relevance to the research topic and novelty. We added the descriptions about the existing GWAS in Introduction section and cited two articles presenting Manhattan plots for CKD risk alleles as references. #1-6 Thank you for your important comment. The reviewer highlighted the necessity for validation regarding the universal applicability across diverse ethnic groups. The authors fully agree with these concerns. Consequently, we are currently undertaking a PRS study utilizing the East Asian population from the Korean Genome and Epidemiology Study (KoGES) and BioBank Japan (BBJ). In addition, we are trying to develop a multi-ethnicity CKD PRS by simultaneously utilizing GWAS summary statistics from Asian and Western populations. Unfortunately, we have not established yet the full datasets, so it is not practical to validate the results of this study in other ethnic groups in the limited timeframe available. We've added these limitations to the Discussion section. Reviewer #2: #2-1 Thank you for the valuable comment. The authors acknowledge these concerns. We conducted a re-analysis by incorporating a variable of fibrate use into the multivariable model, and additionally included fasting time as additional covariate, considering the significant relationship between fasting status and triglyceride level. Subsequent re-analysis results revealed that the impact of each lipid level on CKD and the interactions between lipid levels and PRS were largely consistent with the initial analysis. Consequently, corresponding adjustments were made to Table 1, 2, 3, 4, and Figure 2 to reflect the updated content. The description of these findings in the Results section has also been revised. Attachments Attachment Submitted filename: Rebuttal letter.docx https://doi.org/10.1371/journal.pone.0299605.r002
16 Jan 2024 Decision Letter - Marcelo Arruda Nakazone, Editor PONE-D-23-23585R1Association between dyslipidemia and the risk of incident chronic kidney disease affected by genetic susceptibility: polygenic risk score analysisPLOS ONE Dear Dr. Lee, 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. ============================== ACADEMIC EDITOR: Previous comments have been addressed, but the manuscript will require minor revisions. While recognizing the potential interest of the subject studied, one of the reviewers raised additional comments that need to be properly addressed. ============================== Please submit your revised manuscript by Mar 01 2024 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, Marcelo Arruda Nakazone, M.D., Ph.D. Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] 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 #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? 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 #2: Yes Reviewer #3: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes Reviewer #3: Yes ****** 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 #2: Yes Reviewer #3: Yes ****** 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 #2: Yes Reviewer #3: Yes ****** 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 #2: Thank you. The authors addressed all my concerns. I have no further comments. Reviewer #3: Thanks for your work on an interesting topic. You should underline more the limitations of the UK Biobank as history of diabetes and history of diabetes aren't sufficient enough to reflect the level of BP and/or glycemic time-exposure which should play a role in the occurence of kidney disease. Therefore the discussion should provide a complete overview of all biases for the readers, underlying that further specific research is warranted. ****** 7. 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 #2: No Reviewer #3: Yes: Pierre SABOURET ******** [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.0299605.r003
Revision 2
6 Feb 2024 Author Response <Response to Editor> Thank you for the comment. We have reviewed the reference list and found a correction in reference number 31. This correction was due to an error in electronic tagging and did not change the content of the article. However, after review, we changed the reference to a more appropriate reference and made the following changes to the reference list of the manuscript: - Original Reference 31: Ebrahim S, Sung J, Song YM, Ferrer RL, Lawlor DA, Davey Smith G. Serum cholesterol, haemorrhagic stroke, ischaemic stroke, and myocardial infarction: Korean national health system prospective cohort study. Bmj. 2006;333(7557):22. Epub 2006/06/08. http://doi.org/10.1136/bmj.38855.610324.80 - Revised Reference 31: Miller M. Dyslipidemia and cardiovascular risk: the importance of early prevention. QJM. 2009;102(9):657-67. Epub 2009/06/04. http://doi.org/10.1093/qjmed/hcp065 <Response to Reviewer #3> Thank you for the valuable comment. In response the comment, we further explained the limitations of not having a time exposure factor for diabetes and hypertension in the Discussion section, emphasizing the need for further research: “Furthermore, information regarding the timing of diagnosis of diabetes and hypertension was not available from the UK Biobank, variables regarding the duration of exposure to hyperglycemia and high blood pressure, which are important in the development of kidney disease, could not be applied to the analysis. Further cohort studies, including more precise and regular assessments of clinical and lifestyle data incorporating temporal information, are warranted.” Attachments Attachment Submitted filename: Rebuttal letter 0207ljh.docx https://doi.org/10.1371/journal.pone.0299605.r004
14 Feb 2024 Decision Letter - Marcelo Arruda Nakazone, Editor Association between dyslipidemia and the risk of incident chronic kidney disease affected by genetic susceptibility: polygenic risk score analysis PONE-D-23-23585R2 Dear Dr. Lee, 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, 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 #3: All comments have been addressed ******** 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 #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: Yes ****** 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 #3: Yes ****** 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 #3: Yes ****** 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 #3: Dear author, you clearly answered to all comments. This article may be accepted for a publication in PlosOne. Further research is warranted to better define the causation btw lipid profiles, PRS and CKD. Congratulations for your work. ****** 7. 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 #3: Yes: SABOURET Pierre ******** https://doi.org/10.1371/journal.pone.0299605.r005
Formally Accepted
2 Apr 2024 Acceptance Letter - Marcelo Arruda Nakazone, Editor PONE-D-23-23585R2 PLOS ONE Dear Dr. Lee, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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 Professor Marcelo Arruda Nakazone Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0299605.r006

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