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. 2021 Apr 7;16(4):e0249494. doi: 10.1371/journal.pone.0249494

O group is a protective factor for COVID19 in Basque population

Maider Muñoz-Culla 1, Andres Roncancio-Clavijo 2, Bruno Martínez 3, Miriam Gorostidi-Aicua 1, Luis Piñeiro 4, Arkaitz Azkune 5, Ainhoa Alberro 1, Jorge Monge-Ruiz 6, Tamara Castillo-Trivino 1,2,3,4,5,6,7, Alvaro Prada 2, David Otaegui 1,*
Editor: Raffaele Serra8
PMCID: PMC8026022  PMID: 33826662

Abstract

ABO blood groups have recently been related to COVID19 infection. In the present work, we performed this analysis using data from 412 COVID19 patients and 17796 blood donors, all of them from Gipuzkoa, a region in Northern Spain. The results obtained confirmed this relation, in addition to showing a clear importance of group O as a protective factor in COVID19 disease, with an OR = 0.59 (CI95% 0.481–0.7177, p<0.0001) while A, B and AB are risk factors. ABO blood groups are slightly differently distributed in the populations and therefore these results should be replicated in the specific areas with a proper control population.

Introduction

COVID19 is a pandemic disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This disease has rapidly become the most important world health challenge in the last century.

Despite an incredible and collaborative research effort in the last months, the pathogenesis and the clinical symptoms of COVID19 are poorly understood. Several works have been published to understand the great heterogeneity in the infection and the clinical manifestations of SARS-CoV-2 in different patients. Several biomarkers have been proposed as risk or protective factors. In this scenario, a recent paper, demonstrating the importance of collaborative networks, presents the results of a Genome-wide analysis focused on COVID19 patients [1]. One of the associated loci in chromosome 9, point to an association between ABO blood group and risk of infection by SARS-CoV-2. This association with the ABO blood group has been previously reported in other series showing that Group A is a risk factor while Group O seems to be a protective factor against SARS-CoV-2 infection.

ABO groups are distributed differently based on ethnic origin and, therefore, the results from these studies are highly dependent on the distribution followed by the control group in each region. With this in mind, the main aim of this short report is to study the ABO group distribution in COVID19 patients in the region of Gipuzkoa (Basque country).

Methods

Blood groups from COVID19 patients were anonymously retrieved from electronic clinical history. All the included patients were symptomatic and had tested positive for SARS-CoV-2 infection by qPCR technique at the Microbiology Department of Donostia University Hospital. The kits used for the qPCR came from different suppliers and all of them are approved for diagnostic purposes.

The distribution of the ABO groups from COVID19 patients was compared to that from the general Basque population, obtained from the Basque Blood Bank database and preserving the anonymity of all the participants. Both the anonymous data and the realization of the project have been approved by “the OSI Donostialdea Ethical Committee in Clinical Research” (Code: API-GRA-2020-01). Besides, the used information and methodology are in accordance with the adequate guidelines and regulations.

When analyzing the data, SPSS software was used (v 20) and for the analysis of the distribution chi-square test was applied.

Patients were divided by groups based on severity, following the next criteria: they were characterized as Mild cases when clinical symptoms were moderate with no signs of pneumonia on imaging. Moderate cases, instead, were those individuals that manifested fever and respiratory symptoms and showed radiological findings of pneumonia. Finally, Severe cases were those meeting any of the following criteria: (1) Respiratory distress (≧30 breaths/ min); (2) Oxygen saturation≤93% at rest; (3) Arterial partial pressure of oxygen (PaO2)/ fraction of inspired oxygen (FiO2)≦300mmHg (l mmHg = 0.133kPa). This classification was based on the one proposed by the Chinese National Health Commission on March 3, 2020 [2].

Results

Our cohort includes 412 COVID19 patients and 17796 anonymous blood donors from the same geographical area (Gipuzkoa). The average age of COVID19 patients is 57.64 years, with a 68.45% of women. Referring to severity, 49.29% of the patients were characterized as moderate, 8.92% as mild and 41.78% as severe.

The distribution of the ABO groups is shown in Table 1. In line with the published works, our results also show a higher frequency of group A in COVID19 patients when compared to control group, in this case Basque population, (48.3% vs 40.65%, p = 0.00179), while group O is less represented (39.08 vs 52.19%, p<0.0001). The group A presents an OR of 1.36 (CI95% 1.12–1.66, p = 0.0019), while O group’s OR is 0.5876 (CI95% 0.481–0.7177, p<0.0001). Group B and AB also show a significantly different distribution (p = 0.00186 and p = 0.012204) with an OR = 1.76 (CI95% 1.24–2.49) and OR = 1.98 (CI95% 1.19–3.31), respectively. Nonetheless, since those groups are less frequent in the population, these results should be taken with caution.

Table 1. ABO group distribution in the Gipuzkoa cohort.

A B AB O TOTAL
Blood donors 40.65% (7235) 5.16% (918) 1.20% (355) 52.19% (9288) 17796
COVID19 patients 48.30% (199) 8.74% (36) 3.88% (16) 39.08% (161) 412
p-value 0.00179 0.00186 0.012204 <0.0001
COVID19 patients A B AB O TOTAL
Moderate 48.57%(51) 50.00% (8) 45.54% (5) 50.62%(41) 105
Light 10.48%(11) 6.25%(1) 0.00%(0) 8.64%(7) 89
Severe 40.95%(43) 43.75%(7) 54.55%(6) 40.74%(33) 19
p-value n.s. 213
Open in a new tab

P-values from the Chi-square test are shown for the comparison of each group distribution in blood donors vs COVID19 patients. ns = No significant (p value >0.05).

Furthermore, if ABO group is analyzed as a dichotomous variable; defined as having any antigen (A,B and AB) or none (O); the results highlight the protective role of group O, being the OR for no-O equal to 1.7019 (CI95% 1.94–2.08, p<0.0001). No difference has been found in ABO group distribution with severity.

Discussion

Our data shows the importance of the absence of immune antigens defined by group O, as a protective factor for Sars-CoV-2 virus infection. These results are consistent with the preprinted works conducted in the Chinese population [3] and in the New York cohort [4], and also with the genotyping studies performed in the Italian and Spanish population (including samples from Gipuzkoa). Due to the different distribution of the ABO groups by ethnicity, the validation of these kind of observations, in each region and with the proper controls, is important to achieve a better understanding of how the virus is spreading in the population. In our study, the group O distribution differs from that of other series, seeming more protective in the population from Gipuzkoa. In Fig 1 we represent the differences between the populations in the two more represented blood groups (O and A).

Fig 1. Odd ratio of A (red square) and O group (green circle) from our study and the ones found in the literature.

Fig 1

Open in a new tab

The observed different distribution seems to be related to the infection event and not to the course of the disease. The mechanisms behind these observations remain unknown. It has been proposed that the presence of anti-A Antibodies could be protective against viral entry into lung epithelium or that it may be the fact that O group presents an altered glycosiltransferase activity and, therefore, an increased clearance of Von Willebrand factor, that could protect O group patients from the COVID19- related microvascular thrombosis and endothelial dysfunction [5].

In conclusion, our data confirms the idea that O group is a protective factor for COVID19, and the presence of any antigen (A, B and AB) are a risk factor to suffer the disease. Our results also support the need for further studies in each region with proper population controls. The biological implications of these observations deserve future investigations to shed light on the mechanisms behind COVID19 infection risk.

Acknowledgments

Authors want to thank all the clinicians that have worked so hard these last months and to all the COVID19 patients.

Data Availability

All relevant data are within the manuscript.

Funding Statement

This project has been supported by Instituto de Salud Carlos III (COV20/00314) that includes European Support (FEDER). There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.Ellinghaus D, Degenhardt F, Bujanda L, Buti M, Albillos A, Invernizzi P, et al. Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N Engl J Med. 2020; NEJMoa2020283. 10.1056/NEJMoa2020283 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.On NHC& SA of TCM. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumoniae. (trial version 7). 2020. [DOI] [PMC free article] [PubMed]
  • 3.Zhao J, Yang Y, Huang H-P, Li D, Gu D-F, Lu X-F, et al. Relationship between the ABO Blood Group and the COVID-19 Susceptibility. medRxiv. 2020; 2020.03.11.20031096. 10.1101/2020.03.11.20031096 [DOI] [Google Scholar]
  • 4.Zietz M, Tatonetti NP. Testing the association between blood type and COVID-19 infection, intubation, and death. medRxiv. 2020; 2020.04.08.20058073. 10.1101/2020.04.08.20058073 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Patrice Guillon 1 MCVSJ-GRC-FCNR-CJLP. Inhibition of the Interaction Between the SARS-CoV Spike Protein and Its Cellular Receptor by Anti-Histo-Blood Group Antibodies—PubMed. Glycobiology. 2008;18: 1085–1093. Available: https://pubmed.ncbi.nlm.nih.gov/18818423/ 10.1093/glycob/cwn093 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Raffaele Serra

4 Dec 2020

PONE-D-20-36036

O Group is a protective factor for COVID19 in Basque population

PLOS ONE

Dear Dr. Otaegui,

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.

The article is interesting but it needs some extra work before it can be accepted.

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Academic Editor

PLOS ONE

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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

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

Reviewer #1: Yes

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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.

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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: In this study, the authors compare the distributions of blood group types in (apparently) symptomatic COVID19 patients diagnosed in Gipuzkoa (Basque country, Spain) with the distributions of blood group types found in the general population, as inferred from a local Basque blood bank. They conclude that O blood group is protective, whereas A blood group is a risk factor. This study joins a handful of others, from various parts of the world, confirming an influence of blood group on vulnerability to COVID19 infection.

I have a few suggestions for the authors to consider:

1. In the abstract, I would suggest moving what is currently the second sentence (the call for replication of the work in different regions of the world) to the end of the abstract text, after the main results have been presented. I would also encourage the authors to give, in the abstract, some quantification of the degree of protection conferred by group O blood (e.g, the odds ratio).

2. The authors state that all patients had tested positive for SARS-CoV-2 infection at Donostia University Hospital “according to the actual guidelines.” Could they please describe briefly those guidelines? Were these patients symptomatic, asymptomatic, or a mix of the two? Later, in the results, it appears that all the COVID patients had some level of clinical symptoms, but it would be good to clarify that asymptomatic individuals were excluded from the study, if that is indeed the case.

3. The results section states “According with the literature, in our data group A is more frequent in COVID19 patients (48.3% . . . )”; the authors need to be explicit that they are comparing this with the frequency of group A in the general Basque population.

4. I think the authors could add value to their paper by testing whether blood groups A, B, and AB differ from each other in terms of susceptibility to COVID infection. The authors emphasize group A, but it seems like group B might be still more susceptible, and AB perhaps the most susceptible.

5. The authors state that “No difference has been found in ABO group distribution with severity”, but the readers cannot evaluate this claim, because the data are not shown. I would encourage the authors to include the data broken down into severity categories, along with some formal statistical analysis of disease severity effects. This could be done in an on-line electronic supplement if the authors don’t wish to include it in the main text of the manuscript.

6. The manuscript needs a final light editing to correct numerous small problems with English grammar. (I would have called some of these out, but my copy of the manuscript does not have line numbers.)

**********

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Reviewer #1: No

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PLoS One. 2021 Apr 7;16(4):e0249494. doi: 10.1371/journal.pone.0249494.r002

Author response to Decision Letter 0

26 Jan 2021

POINT-BY-POINT RESPONSE TO THE REVIEWERS

Reviewer #1

In this study, the authors compare the distributions of blood group types in (apparently) symptomatic COVID19 patients diagnosed in Gipuzkoa (Basque country, Spain) with the distributions of blood group types found in the general population, as inferred from a local Basque blood bank. They conclude that O blood group is protective, whereas A blood group is a risk factor. This study joins a handful of others, from various parts of the world, confirming an influence of blood group on vulnerability to COVID19 infection.

I have a few suggestions for the authors to consider:

1. In the abstract, I would suggest moving what is currently the second sentence (the call for replication of the work in different regions of the world) to the end of the abstract text, after the main results have been presented. I would also encourage the authors to give, in the abstract, some quantification of the degree of protection conferred by group O blood (e.g, the odds ratio).

We thank to the reviewer for this comment. As suggested we change the abstract and add the required information.

2. The authors state that all patients had tested positive for SARS-CoV-2 infection at Donostia University Hospital “according to the actual guidelines.” Could they please describe briefly those guidelines? Were these patients symptomatic, asymptomatic, or a mix of the two? Later, in the results, it appears that all the COVID patients had some level of clinical symptoms, but it would be good to clarify that asymptomatic individuals were excluded from the study, if that is indeed the case.

Thanks for the comment. We added this information to the method section of the manuscript to clarify that all the COVID19 patients included in the study were symptomatic and how the positivity for the virus was tested. Approved SARS_CoV-2 qPCR test has been performed for all the samples at Microbiology department in the Donostia University Hospital. The moment in which all data for this study were retrieved, was a moment in the pandemic in which all the patients that came to the Hospital were Symptomatic.

3. The results section states “According with the literature, in our data group A is more frequent in COVID19 patients (48.3% . . . )”; the authors need to be explicit that they are comparing this with the frequency of group A in the general Basque population.

Thanks for notice it. We have added this to the manuscript and have rewritten the sentence to avoid any misunderstanding.

4. I think the authors could add value to their paper by testing whether blood groups A, B, and AB differ from each other in terms of susceptibility to COVID infection. The authors emphasize group A, but it seems like group B might be still more susceptible, and AB perhaps the most susceptible.

We change our results section adding tests for each group.

5. The authors state that “No difference has been found in ABO group distribution with severity”, but the readers cannot evaluate this claim, because the data are not shown. I would encourage the authors to include the data broken down into severity categories, along with some formal statistical analysis of disease severity effects. This could be done in an on-line electronic supplement if the authors don’t wish to include it in the main text of the manuscript.

We add in Table 1 a distribution of the ABO groups with severity.

6. The manuscript needs a final light editing to correct numerous small problems with English grammar. (I would have called some of these out, but my copy of the manuscript does not have line numbers.)

Thanks to the reviewer for the comment. We have reviewed the manuscript and polish the language, so we hope that now the English grammar is correct.

Attachment

Submitted filename: reponse to the reviewers_ABOgroups_MMC.docx

Click here for additional data file. (14.5KB, docx)

Decision Letter 1

Raffaele Serra

9 Feb 2021

PONE-D-20-36036R1

O Group is a protective factor for COVID19 in Basque population

PLOS ONE

Dear Dr. Otaegui,

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.

The manuscript was improved but it needs further revision as suggested by the reviewer.

Please submit your revised manuscript by Mar 26 2021 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Prof. Raffaele Serra, M.D., Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

While the manuscript was improved it needs further reworking.

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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: (No Response)

**********

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: Partly

**********

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

Reviewer #1: 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 #1: 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 #1: No

**********

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: I reviewed this manuscript previously, so my current reading emphasized looking for changes since the first draft. The reviewers successfully implemented many changes, and I think this revision is improved.

I do think, however, that given that the new analyses shown in Table 1 now show that blood types B and AB are even greater risk factors than blood type A, the rest of the discussion in the manuscript (which emphasizes effects of blood group A and ignores B and AB) seems now incomplete and not quite appropriate. I would encourage the authors to modify the discussion to reflect their results: O is protective, and A and especially B are risk factors.

The authors also mention in passing that there seems to be a higher risk of infection for men. If they wish to make this point, I think they should support it with some sort of quantitative statistical test. Given that men and women may have different exposures to infection or different likelihoods of seeking medical care when sick, I don’t know how strong the evidence in Table 1 really is with regards to effects of sex. I’d encourage the authors to make a decision to either (1) choose to introduce the question of differential vulnerability to infection, and then formally test it, or (2) omit the issue altogether, and instead focus only on blood group. (Option 2 might be the best, but it’s really up to the authors.)

The manuscript still does not have line numbers, making it very difficult for me to suggest fixes to small grammatical errors. The paper still needs a final editing to correct numerous small problems.

**********

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

[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.

PLoS One. 2021 Apr 7;16(4):e0249494. doi: 10.1371/journal.pone.0249494.r004

Author response to Decision Letter 1

2 Mar 2021

POINT-BY-POINT RESPONSE TO THE REVIEWER

Reviewer #1

Reviewer #1: I reviewed this manuscript previously, so my current reading emphasized looking for changes since the first draft. The reviewers successfully implemented many changes, and I think this revision is improved.

We want to thanks the reviewer by her/his help to improve our manuscript.

I do think, however, that given that the new analyses shown in Table 1 now show that blood types B and AB are even greater risk factors than blood type A, the rest of the discussion in the manuscript (which emphasizes effects of blood group A and ignores B and AB) seems now incomplete and not quite appropriate. I would encourage the authors to modify the discussion to reflect their results: O is protective, and A and especially B are risk factors.

We agree with the reviewer that blood type B and even AB seems to be risk factor, however me try to focus our discussion in A and O group that are the two more represented in our patient’s population. Blood type B is only present in 36 patients and AB in 16 and that why we focus in the other 2 blood groups. We change our discussion to include the observation about B and AB group.

The authors also mention in passing that there seems to be a higher risk of infection for men. If they wish to make this point, I think they should support it with some sort of quantitative statistical test. Given that men and women may have different exposures to infection or different likelihoods of seeking medical care when sick, I don’t know how strong the evidence in Table 1 really is with regards to effects of sex. I’d encourage the authors to make a decision to either (1) choose to introduce the question of differential vulnerability to infection, and then formally test it, or (2) omit the issue altogether, and instead focus only on blood group. (Option 2 might be the best, but it’s really up to the authors.)

Thanks to the reviewer for this comment. We thought that could be interesting for the readers to have the data by gender but we are totally agree with the reviewer that with our experimental design we cannot say that men shows a higher infection and may be the data can reflect the effect of other issues. Therefore, to focus in the point that we think is more interesting, we rewrite the paragraph and the Table 1 to show just the data from patients vs controls.

The manuscript still does not have line numbers, making it very difficult for me to suggest fixes to small grammatical errors. The paper still needs a final editing to correct numerous small problems.

The manuscript has been reviewed by different persons to correct the grammatical problems and do it more readable. Line numbers had been included.

Decision Letter 2

Raffaele Serra

19 Mar 2021

O Group is a protective factor for COVID19 in Basque population

PONE-D-20-36036R2

Dear Dr. Otaegui,

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.

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PLOS ONE

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Reviewer #1: All comments have been addressed

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Reviewer #1: Yes

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Reviewer #1: I think the revision is very successful in providing a more balanced discussion of the risk associated with A, B, and AB blood groups.

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Acceptance letter

Raffaele Serra

29 Mar 2021

PONE-D-20-36036R2

O Group is a protective factor for COVID19 in Basque population

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