Loss of Y in leukocytes as a risk factor for critical COVID-19 in men
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Abstract
Background
The COVID-19 pandemic, which has a prominent social and economic impact worldwide, shows a largely unexplained male bias for the severity and mortality of the disease. Loss of chromosome Y (LOY) is a risk factor candidate in COVID-19 due to its prior association with many chronic age-related diseases, and its impact on immune gene transcription.
Methods
Publicly available scRNA-seq data of PBMC samples derived from male patients critically ill with COVID-19 were reanalyzed, and LOY status was added to the annotated cells. We further studied LOY in whole blood for 211 COVID-19 patients treated at intensive care units (ICU) from the first and second waves of the pandemic. Of these, 139 patients were subject to cell sorting for LOY analysis in granulocytes, low-density neutrophils (LDNs), monocytes, and PBMCs.
Results
Reanalysis of available scRNA-seq data revealed LDNs and monocytes as the cell types most affected by LOY. Subsequently, DNA analysis indicated that 46%, 32%, and 29% of critically ill patients showed LOY above 5% cut-off in LDNs, granulocytes, and monocytes, respectively. Hence, the myeloid lineage that is crucial for the development of severe COVID-19 phenotype is affected by LOY. Moreover, LOY correlated with increasing WHO score (median difference 1.59%, 95% HDI 0.46% to 2.71%, p =0.025), death during ICU treatment (median difference 1.46%, 95% HDI 0.47% to 2.43%, p =0.0036), and history of vessel disease (median difference 2.16%, 95% HDI 0.74% to 3.7%, p =0.004), among other variables. In 16 recovered patients, sampled during ICU stay and 93–143 days later, LOY decreased significantly in whole blood and PBMCs. Furthermore, the number of LDNs at the recovery stage decreased dramatically (median difference 76.4 per 10,000 cell sorting events, 95% HDI 55.5 to 104, p =6e−11).
Conclusions
We present a link between LOY and an acute, life-threatening infectious disease. Furthermore, this study highlights LOY as the most prominent clonal mutation affecting the myeloid cell lineage during emergency myelopoiesis. The correlation between LOY level and COVID-19 severity might suggest that this mutation affects the functions of monocytes and neutrophils, which could have consequences for male innate immunity.
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SciScore for 10.1101/2022.01.19.22269521: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Informed consent was obtained from all the participants, or from next of kin for ICU-admitted patients, who were not able to give consent themselves.
IRB: The research was approved by the local research ethics committee in Uppsala and Gothenburg, Sweden Dnr. 2017/043 with amendments 2019/00169, 2020-01623, 2020-20719 and 2021-01469; Dnr. 2020-01771 (COVID-19 cohorts) and Dnr. 2021-02205 (COVID-19 recovery samples).
Field Sample Permit: NKBBN/564/2018 approved sample collection for control cohort in Poland.Sex as a biological variable Study design, sample collection and clinical variables: Male patients with COVID-19 were enrolled in Sweden, at Uppsala University Hospital (as part of … SciScore for 10.1101/2022.01.19.22269521: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Informed consent was obtained from all the participants, or from next of kin for ICU-admitted patients, who were not able to give consent themselves.
IRB: The research was approved by the local research ethics committee in Uppsala and Gothenburg, Sweden Dnr. 2017/043 with amendments 2019/00169, 2020-01623, 2020-20719 and 2021-01469; Dnr. 2020-01771 (COVID-19 cohorts) and Dnr. 2021-02205 (COVID-19 recovery samples).
Field Sample Permit: NKBBN/564/2018 approved sample collection for control cohort in Poland.Sex as a biological variable Study design, sample collection and clinical variables: Male patients with COVID-19 were enrolled in Sweden, at Uppsala University Hospital (as part of the PronMed-study) and Sahlgrenska University Hospital in Gothenburg with confirmed positive SARS-CoV-2 nasopharyngeal test verified by RT-PCR. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources Data were acquired and analyzed using BD FACSDiva™ Software (Becton Dickinson) BD FACSDiva™suggested: (BD FACSDiva Software, RRID:SCR_001456)Differential expression tests: Differential expression (DE) tests were performed in CD14+ monocytes using FindMarker functions in Seurat with a hurdle model tailored to sc-RNA-seq data in MAST. MASTsuggested: (MAST, RRID:SCR_016340)Among the top 100 significant DEGs, 21 DEGs showing a down pattern were taken as a gene set for enrichment test by R/enrichR package vs. R/enrichRsuggested: NoneGO Biological Process 2021 (GO:BP2021) and vs. GO Molecular Function 2021 (GO:MF2021). GO Biologicalsuggested: NoneResults from OddPub: Thank you for sharing your code.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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