The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in [ME/CFS].., 2021, Malato et al

[Andy]

Full title: The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: analysis of high-throughput genetic, epigenetic, and gene expression studies

Abstract

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) show specific epigenetic and gene expression signatures of the disease. However, it is unknown whether these signatures in ME/CFS include abnormal levels of the human angiotensin-converting enzyme ACE and ACE2, the latter being the main receptor described for host-cell invasion by SARS-CoV-2.

To investigate that, we first reviewed published case-control genome-wide association studies based on single nucleotide polymorphism data, case-control epigenome-wide association studies based on DNA methylation data, and case-control gene expression studies based on microarray data. From these published studies, we did not find any evidence for a difference between patients with ME/CFS and healthy controls in terms of genetic variation, DNA methylation, and gene expression levels of ACE and ACE2.

In line with this evidence, the analysis of a new data set on the ACE/ACE2 gene expression in peripheral blood mononuclear cells did not find any differences between a female cohort of 37 patients and 34 age-matched healthy controls.

Future studies should be conducted to extend this investigation to other potential receptors used by SARS-CoV-2. These studies will help researchers and clinicians to better assess the health risk imposed by this virus when infecting patients with this debilitating disease.

https://www.medrxiv.org/content/10.1101/2021.03.23.21254175v1.full-text

Line breaks added for easier reading.

 

[Snow Leopard]

I'm not sure why they thought there would be a difference, but better to know than not know, right?

 

[Hutan]

I think they were checking out an old finding:

Interestingly, ACE levels were found to be elevated in about 80% of patients diagnosed with an old case definition of ME/CFS (Lieberman and Bell, 1993). Such observation suggested this enzyme as a possible biomarker for the disease.

I was interested in this, as the two times my level of ACE was tested, it was slightly high.

To me, it seems that the authors tried to do a solid study. They reviewed previous studies covering ACE in ME/CFS, appearing to understand good practice in the gene expression evaluation techniques, and also to understand the importance of well-characterised patients (e.g. they excluded studies where participants self-reported ME/CFS, required Fukuda or CCC diagnosis).

This was an interesting comment:

In addition, there were four case-control GES using RNA-seq technologies (Bouquet et al., 2019, 2017; Raijmakers et al., 2019; Sweetman et al., 2019). However, they were excluded from further analysis due to the lack of basic quality control checks such as the percentage of reads that could be mapped onto the reference transcriptome, the percentage of the transcriptome covered, the average number of mapped reads per transcript, any effect of the GC content on the mapped read distribution, as recommended elsewhere (Conesa et al., 2016).

 

[Hutan]

There are some good comments on how these studies could be done better e.g.this one on making data publicly available:

Fourthly, only a few of the published studies made their data publicly available, which we could use in our investigation. This issue was particularly limiting for GWAS, because none of these studies deposited the data in any open-access data repository. Currently, many funders and other science-related stakeholders are supporting the reuse and the long-term maintenance of scientific data generated by publicly funded research (Wilkinson et al., 2016).

Above all, the benefit of a wide data-sharing practice is expected to accelerate scientific knowledge and to boost confidence in findings by allowing other researchers to take a fresh look at the same data. It could also promote collaboration among researchers, and to make science open to everyone, specifically, when it is funded by taxpayers and charities. Data sharing is also essential to cut down the costs of research by sharing resources among the research community. Reducing the costs of research by sharing limited resources is particularly important for the underfunded ME/CFS research field, as discussed above.

 

[Hutan]

This was an interesting paragraph that concludes
"Therefore, perturbations of the normal levels of DPP4 would appear to be a hallmark of ME/CFS pathogenesis."

Dipeptidyl peptidase-4 (DPP4), also known as lymphocyte cell surface protein CD26, was found to be the main functional receptor for the host-cell entry by MERS (van Doremalen et al., 2014; Widagdo et al., 2019). This molecule is highly expressed in PBMCs including CD4+ and CD8+ T cells (Radzikowska et al., 2020). It is then possible that SARS-CoV-2 is able to infect PBMCs via a route involving DPP4 rather than ACE2. Interestingly, a study reported an increased proportion of natural killers and T cells expressing DPP-4/CD26+ in patients with CFS when compared to healthy controls (Klimas et al., 1990). A follow-up study confirmed this finding but also showed evidence for a decreased number of CD26 molecules in T lymphocytes and natural killer cells of patients with ME/CFS (Fletcher et al., 2010). The same study suggested a decreased level of the soluble form of the molecule in the serum from patients. Similar observation was found in a recent study, but specifically for female patients whose disease was initiated after an infection (Szklarski et al., 2021). Therefore, perturbations of the normal levels of DPP4 would appear to be a hallmark of ME/CFS pathogenesis.

 

[Andy]

Now published, open access, https://www.cell.com/heliyon/fulltext/S2405-8440(21)01768-0

 

[mango]

https://meassociation.org.uk/2021/0...r-risk-of-complications-from-covid-infection/

 

[Hutan]

Now published, open access, https://www.cell.com/heliyon/fulltext/S2405-8440(21)01768-0

That new link takes you to:

The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in myalgic encephalomyelitis/chronic fatigue syndrome: A meta-analysis of public DNA methylation and gene expression data

Abstract

People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report a high frequency of viral infections and flu-like symptoms during their disease course. Given that this reporting agrees with different immunological abnormalities and altered gene expression profiles observed in the disease, we aimed at answering whether the expression of the human angiotensin-converting enzyme 2 (ACE2), the major cell entry receptor for SARS-CoV-2, is also altered in these patients. In particular, a low expression of ACE2 could be indicative of a high risk of developing COVID-19.

We then performed a meta-analysis of public data on CpG DNA methylation and gene expression of this enzyme and its homologous ACE protein in peripheral blood mononuclear cells and related subsets. We found that patients with ME/CFS have decreased methylation levels of four CpG probes in the ACE locus (cg09920557, cg19802564, cg21094739, and cg10468385) and of another probe in the promoter region of the ACE2 gene (cg08559914). We also found a decreased expression of ACE2 but not of ACE in patients when compared to healthy controls.

Accordingly, in newly collected data, there was evidence for a significant higher proportion of samples with an ACE2 expression below the limit of detection in patients than healthy controls. Altogether, patients with ME/CFS can be at a higher COVID-19 risk and, if so, they should be considered a priority group for vaccination by public health authorities. To further support this conclusion, similar research is recommended for other human cell entry receptors and cell types, namely, those cells targeted by the virus.​

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It looks like this is a different paper, or a significant re-write. The abstract in the first post says:

From these published studies, we did not find any evidence for a difference between patients with ME/CFS and healthy controls in terms of genetic variation, DNA methylation, and gene expression levels of ACE and ACE2.

I don't know what's going on, but the findings of the two papers are different.