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Blood DNA methylation in post-acute sequelae of COVID-19 PASC: a prospective cohort study, 2024, Balnis et al.

Discussion in 'Long Covid research' started by SNT Gatchaman, Jul 19, 2024.

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  1. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Blood DNA methylation in post-acute sequelae of COVID-19 PASC: a prospective cohort study
    Joseph Balnis; Andy Madrid; Lisa A. Drake; Rachel Vancavage; Anupama Tiwari; Vraj J. Patel; Ramon Bossardi Ramos; John J. Schwarz; Recai Yucel; Harold A. Singer; Reid S. Alisch; Ariel Jaitovich

    BACKGROUND
    DNA methylation integrates environmental signals with transcriptional programs. COVID-19 infection induces changes in the host methylome. While post-acute sequelae of COVID-19 (PASC) is a long-term complication of acute illness, its association with DNA methylation is unknown. No universal blood marker of PASC, superseding single organ dysfunctions, has yet been identified.

    METHODS
    In this single centre prospective cohort study, PASC, post-COVID without PASC, and healthy participants were enrolled to investigate their symptoms association with peripheral blood DNA methylation data generated with state-of-the-art whole genome sequencing. PASC-induced quality-of-life deterioration was scored with a validated instrument, SF-36. Analyses were conducted to identify potential functional roles of differentially methylated loci, and machine learning algorithms were used to resolve PASC severity.

    FINDINGS
    103 patients with PASC (22.3% male, 77.7% female), 15 patients with previous COVID-19 infection but no PASC (40.0% male, 60.0% female), and 27 healthy volunteers (48.1% male, 51.9% female) were enrolled. Whole genome methylation sequencing revealed 39 differentially methylated regions (DMRs) specific to PASC, each harbouring an average of 15 consecutive positions, that differentiate patients with PASC from the two control groups. Motif analyses of PASC-regulated DMRs identify binding domains for transcription factors regulating circadian rhythm and others. Some DMRs annotated to protein coding genes were associated with changes of RNA expression. Machine learning support vector algorithm and random forest hierarchical clustering reveal 28 unique differentially methylated positions (DMPs) in the genome discriminating patients with better and worse quality of life.

    INTERPRETATION
    Blood DNA methylation levels identify PASC, stratify PASC severity, and suggest that DNA motifs are targeted by circadian rhythm-regulating pathways in PASC.

    FUNDING
    This project has been funded by the following agencies: NIH-AI173035 (A. Jaitovich and R. Alisch); and NIH-AG066179 (R. Alisch).


    Link | PDF (Lancet: eBioMedicine) [Open Access]
     
    SNT Gatchaman, Jul 19, 2024
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  2. Hutan

    Hutan Moderator Staff Member

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    I don't know of course, but this study seems really underpowered, given the numbers, especially of the post-Covid-19 controls, and the variable percentages of males in the groups. I would have thought that epigenetics would have a huge amount of noise, with sex right up there as a source of that. Circadian rhythm is mentioned as something regulated by identified transcription regulators, but surely it's possible that, on-average, different lifestyle factors (not working> waking later; more physical activity challenges) might alter the transcription regulators?
     
    Last edited: Jul 20, 2024
    Hutan, Jul 20, 2024
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  3. Hutan

    Hutan Moderator Staff Member

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    A Lancet paper - New York authors

    The authors don't seem to be understanding that PASC is a collection of different things. It's not looking good for a homogenous sample.

    Nope.

     
    Hutan, Jul 20, 2024
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  4. Hutan

    Hutan Moderator Staff Member

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    Table 2: Only around 15% of the PASC people reported fatigue and lack of energy as a reason for attending the clinic. Around 20% of the PASC people reported dyspnea and respiratory issues as a reason for attending the clinic.

    Quite a lot of co-morbidities too.

    CpGs = groups of consecutive positions

    Figure 4 suggests that there are some genes expressed differently in the leukocytes. But see, for example the data for this gene: Screen Shot 2024-07-20 at 8.41.17 pm.png

    Each dot is the data from one person. There does look to be some people with markedly different expression of this gene. And, if we look up FRG2C, it sounds a bit interesting
    FSHD Region Gene 2 Family Member C
    It is associated with
    And, just maybe 'reactive arthritis' has some relevance.

    BUT, 7 of the PASC people have a reported diagnosis of "rheumatic disease" - so a lot of the people with increased expression of the gene probably actually have one of those rheumatic diseases, and it's nothing much to do with PASC at all.
     
    Hutan, Jul 20, 2024
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  5. wabi-sabi

    wabi-sabi Established Member (Voting Rights)

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    The authors don't seem to have a clear understanding of what long COVID is. However, given that all of the people who were still symptomatic after COVID had a different methylation pattern, doesn't that show something of interest?

    Also, from figure 4 above- are they making hay of that result? The PASC mean looks a bit higher to me, but only a tiny bit. And there's so much variability in this data! If we get rid of the outliers, is there a mean difference at all? And what's the difference between the PASC people who look really about the same as the healthy controls and the recovered people and the ones who really do have a different methylation pattern in figure 4?

    Overall, I haven't seen much research on epigenetics and long COVID. Is this a viable area of research or are these people just grasping at straws?
     
    wabi-sabi, Aug 18, 2024
    #5
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