Circulating Polyunsaturated Fatty Acids and COVID-19: A Prospective Cohort Study and Mendelian Randomization Analysis

  1. Yitang Sun
  2. Radhika Chatterjee
  3. Akash Ronanki
  4. Kaixiong Ye

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Abstract

Higher circulating polyunsaturated fatty acids (PUFAs), especially omega-3 fatty acids, have been linked to a better prognosis in patients of coronavirus disease 2019 (COVID-19). However, the effects and causality of pre-infection PUFA levels remain unclear. This study aimed to investigate the observational and causal associations of circulating PUFAs with COVID-19 susceptibility and severity. We first performed a prospective cohort study in UK Biobank, with 20,626 controls who were tested negative and 4,101 COVID-19 patients, including 970 hospitalized ones. Plasma PUFAs at baseline (blood samples collected from 2007 to 2010) were measured by nuclear magnetic resonance, including total PUFAs, omega-3 PUFAs, omega-6 PUFAs, docosahexaenoic acid (DHA), linoleic acid (LA), and the omega-6/omega-3 ratio. Moreover, going beyond UK Biobank, we leveraged summary statistics from existing genome-wide association studies to perform bidirectional two-sample Mendelian randomization (MR) analyses to examine the causal associations of eight individual PUFAs, measured in either plasma or red blood cells, with COVID-19 susceptibility and severity. In the observational association analysis of each PUFA measure separately, total, omega-3, and omega-6 PUFAs, DHA, and LA were associated with a lower risk of severe COVID-19. Omega-3 PUFAs and DHA were also associated with a lower risk of testing positive for COVID-19. The omega-6/omega-3 ratio was positively associated with risks of both susceptibility and severity. When omega-6, omega-3, and their ratio are jointly analyzed, only omega-3 PUFAs remained significantly and inversely associated with both susceptibility and severity. The forward MR analysis indicated that docosapentaenoic acid (DPA-n3) and arachidonic acid (AA) might be causally associated with a lower risk of severe COVID-19, with OR (95% CI) per one SD increase in the plasma level as 0.89 (0.81, 0.99) and 0.96 (0.94, 0.99), respectively. The reverse MR analysis did not support any causal effect of COVID-19 on PUFAs. Our observational analysis supported that higher circulating omega-3 PUFAs, especially DHA, may lower the susceptibility to and alleviate the severity of COVID-19. Our MR analysis further supported causal associations of DPA-n3 and AA with a lower risk of severe COVID-19.

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  1. Version published to 10.3389/fmed.2022.923746
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    SciScore for 10.1101/2022.02.06.22270562: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Ethical considerations: The usage of individual-level data for this study was approved by the University of Georgia Institutional Review Board and UK
    Consent: All participants of UK Biobank and the Framingham Heart Study (FHS) provided written informed consent before joining these studies.
    Sex as a biological variablenot detected.
    RandomizationOur study follows the guidelines for strengthening the reporting of observational studies in epidemiology (STROBE, Supplemental Table 2) and strengthening the reporting of Mendelian randomization studies (STROBE-MR, Supplemental Table 3) (32).
    Blindingnot detected.
    Power AnalysisHowever, MR-Egger can be imprecise and suffer from low statistical power, particularly when based on a small number of SNPs (e.g., < 10) (39).

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All MR analyses were performed in R version 4.0.0 with the TwoSampleMR package version 3.6.9 (44).
    TwoSampleMR
    suggested: (TwoSampleMR, RRID:SCR_019010)

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our study has several limitations. First, we could not completely rule out the possibility that some genetic variants might be pleiotropic, although we applied multiple sensitivity analyses, including the heterogeneity test, MR-Egger, and WM method. Second, a limitation of this MR study is that the effect of endogenous PUFAs may be different from the effect of dietary PUFAs, and our study did not directly examine dietary PUFAs. However, leveraging genetic instruments yields novel insights and minimizes the measurement error from self-reported dietary consumption in nutrition studies. Third, another limitation is that the population controls were utilized with no information on COVID-19 status in three COVID-19 GWAS used in our primary analysis, including the HGI A2, B2, and C2 studies. To mitigate this issue, we also utilized the HGI B1 study, which is another GWAS of COVID-19 using non-hospitalized patients as the control group. Fourth, in the observational study, UK Biobank recruited healthier individuals and thus may not be representative of the general population. Fifth, the NMR-based measurements of plasma PUFAs were collected over ten years before the COVID-19 pandemic, and the time lag likely attenuates the magnitude of association. Sixth, our observational study could be affected by ascertainment bias in differential healthcare seeking and testing. Seventh, our findings might not be extrapolated to other ethnicities because the study only focused on participants of Eu...

    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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  3. Version published to 10.1101/2022.02.06.22270562 on medRxiv