PONE-D-21-24713Absence of association between host genetic mutations in the ORAI1 gene and COVID-19 fatalityPLOS ONE

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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?

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

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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: No

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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

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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: Study based on a biobank dataset to clarify the role of genetic variants within the ORAI1 gene with positivity and mortality for COVID-19. The study design is not clear, the authors do not accurately describe what the main objective is; these aspects should be better defined.

The results demonstrate that there is no significant association between ORAI1 variants and COVID-19 positivity or fatality in the study participants, despite the well-established roles of ORAI1 in immune response and inflammation and the successful inhibition of ORAI1 in clinical studies. Authors should explain the reason for this discrepancy in more detail than they have already done.

Reviewer #2: I am grateful for the chance to review this work by Heba and coworker. The authors retrospectively employed genetic association analysis to investigate the potential association of host genetic 18 polymorphisms of ORAI1 with the risk of developing COVID-19 with COVID-19 fatality in 41146 with British individuals. They found that there was no significant association observed between ORAI1 199 variants and COVID-19 positivity or fatality.

The research question is extremely appealing being the susceptibility to SARS-CoV-2 virus quite unpredictable and given the promising results of the ORAI1 inhibitor in patients with COVID-19. Since study aim is extremely relevant, methodological procedures are correct and statistical analysis is well described and convincing. Manuscript sections are well organized and clear.

I just have a few issues to address:

1) Introduction: in my opinion it should be shortened and focused on the research question.

2) Methods: the frequency of ORAI1 SNpolymorphism should be detailed and considered to estimate a sample large enough to test the research question.

3) Methods: did the authors collected data regarding SARS-CoV-2 major variants? If so, wouldn’t it be interesting to test whether an association with ORAI1 SNP could be find?

4) Methods: the authors should report the percentage of vaccinated people.

4) Results: it is surprising that COVID-19 fatal and non-fatal case have similar average age, gender distribution and hypertension rate. These data are in contrast with the great majority of results reported in literature and should be discussed in more details.

5) Results: Data regarding the prevalence of hearth problem in the COVID-19 fatality group should be checked (just 1 over 332?).

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Reviewer #1: No

Reviewer #2: No

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Absence of association between host genetic mutations in the ORAI1 gene and COVID-19 fatality

PONE-D-21-24713R1

Dear Dr. Bailey,

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,

Alessandro Marchioni

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Professor Bailey,

I am pleased to inform that your paper "Absence of association between host genetic mutations in the ORAI1 gene and COVID-19 fatality" has been revised and considered suitable for publication in PLOS ONE.

CRAC channels have a critical role in the activation of T lymphocytes, and mutations in either Orai1 or STIM1 are characterized by severe immunodeficiency (SCID)-like disease and autoimmunity. Therefore, considering severe COVID-19 the results of a immune response dysregulation, the potential association of genetic polymorphisms of ORAI1 with the risk of Severe Acute Respiratory Syndrome related to SARS-CoV-2 (CARDS) is a relevant topic. Although the authors results suggest that in COVID-19 the host genetic polymorphisms of ORAI1 are unlikely to be implicated in symptoms severity among afflicted patients, we think that the informations provided in the paper could increases the knowledge about this complex disease.

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: (No Response)

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: The authors answered my queries. Even in the presence of significant limitations of the study, I have no other comments to make and it can be published in its current form.

Reviewer #2: I would like to thank the Authors for their responses to my comments. I have no more comments to make.

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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 #1: No

Reviewer #2: Yes: Roberto Tonelli