ACE2 expression in adipose tissue is associated with cardio-metabolic risk factors and cell type composition—implications for COVID-19

  1. Julia S. El-Sayed Moustafa
  2. Anne U. Jackson
  3. Sarah M. Brotman
  4. Li Guan
  5. Sergio Villicaña
  6. Amy L. Roberts
  7. Antonino Zito
  8. Lori Bonnycastle
  9. Michael R. Erdos
  10. Narisu Narisu
  11. Heather M. Stringham
  12. Ryan Welch
  13. Tingfen Yan
  14. Timo Lakka
  15. Stephen Parker
  16. Jaakko Tuomilehto
  17. Jeffrey Seow
  18. Carl Graham
  19. Isabella Huettner
  20. Sam Acors
  21. Neophytos Kouphou
  22. Samuel Wadge
  23. Emma L. Duncan
  24. Claire J. Steves
  25. Katie J. Doores
  26. Michael H. Malim
  27. Francis S. Collins
  28. Päivi Pajukanta
  29. Michael Boehnke
  30. Heikki A. Koistinen
  31. Markku Laakso
  32. Mario Falchi
  33. Jordana T. Bell
  34. Laura J. Scott
  35. Karen L. Mohlke
  36. Kerrin S. Small

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Abstract

Background

COVID-19 severity varies widely. Although some demographic and cardio-metabolic factors, including age and obesity, are associated with increasing risk of severe illness, the underlying mechanism(s) are uncertain.

Subjects/methods

In a meta-analysis of three independent studies of 1471 participants in total, we investigated phenotypic and genetic factors associated with subcutaneous adipose tissue expression of Angiotensin I Converting Enzyme 2 ( ACE2 ), measured by RNA-Seq, which acts as a receptor for SARS-CoV-2 cellular entry.

Results

Lower adipose tissue ACE2 expression was associated with multiple adverse cardio-metabolic health indices, including type 2 diabetes (T2D) ( P  = 9.14 × 10 −6 ), obesity status ( P  = 4.81 × 10 −5 ), higher serum fasting insulin ( P  = 5.32 × 10 −4 ), BMI ( P  = 3.94 × 10 −4 ), and lower serum HDL levels ( P  = 1.92 × 10 −7 ). ACE2 expression was also associated with estimated proportions of cell types in adipose tissue: lower expression was associated with a lower proportion of microvascular endothelial cells ( P  = 4.25 × 10 −4 ) and higher proportion of macrophages ( P  = 2.74 × 10 −5 ). Despite an estimated heritability of 32%, we did not identify any proximal or distal expression quantitative trait loci (eQTLs) associated with adipose tissue ACE2 expression.

Conclusions

Our results demonstrate that individuals with cardio-metabolic features known to increase risk of severe COVID-19 have lower background ACE2 levels in this highly relevant tissue. Reduced adipose tissue ACE2 expression may contribute to the pathophysiology of cardio-metabolic diseases, as well as the associated increased risk of severe COVID-19.

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  1. Version published to 10.1038/s41366-022-01136-w
  2. ScreenIT

    SciScore for 10.1101/2020.08.11.20171108: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableIn the FUSION study, which included both males and females, analyses were also performed in males and females separately, excluding the sex covariate in the models.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Blood/cell-type proportions for each FUSION adipose sample were estimated using the unmix function from DESeq2 v1.18.155.
    DESeq2
    suggested: (DESeq, RRID:SCR_000154)
    METSIM RNASeq data have been deposited in the Gene Expression Omnibus (GEO) under accession GSE135134.
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)

    Results from OddPub: Thank you for sharing your data.

    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.

    About SciScore

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  3. Version published to 10.1101/2020.08.11.20171108v1 on medRxiv