Genetic risk factors of ME/CFS: a critical review

Dibble, Joshua J; McGrath, Simon J.; Ponting, Chris P.

doi:10.1093/hmg/ddaa169

Cited by 33 publications

(46 citation statements)

References 61 publications

(63 reference statements)

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“…Two studies reported many candidate SNPs for such association, but none was located in ACE or ACE2 11 , 86 . Two other studies did not find any significant SNPs associated with ME/CFS 32 , 88 . The most optimistic study reported thousands of SNPs related to the disease [ 87 ].…”

Section: Discussionmentioning

confidence: 83%

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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

Malato

Sotzny

Bauer

et al. 2021

Heliyon

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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. Since this reporting is in line with different immunological abnormalities and altered gene expression profiles observed in the disease, we aimed to explore whether the expression of the human angiotensin-converting enzyme-2 (ACE2), the major cell entry receptor for SARS-CoV-2, is also altered in this neglected clinical population. In particular, a low expression of ACE2 is usually 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 with ME/CFS when compared to healthy controls. Accordingly, in newly collected data, we found evidence for a higher proportion of samples with an ACE2 expression below the limit of detection in patients with ME/CFS than in healthy controls. Altogether, patients with ME/CFS could be at a higher COVID-19 risk when infected by SARS-CoV-2. To further support this conclusion, similar research should be conducted for other human cell entry receptors and other cell types, namely, those mainly targeted by the virus.

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Section: Discussionmentioning

confidence: 83%

“…Finally, our original idea was to perform a meta-analysis of ACE/ACE2 data from published genome-wide association studies on ME/CFS 11 , 32 , 86 , 87 , 88 . However, we could not materialize this idea, because such studies did not make their data publicly available.…”

Section: Discussionmentioning

confidence: 99%

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

Malato

Sotzny

Bauer

et al. 2021

Heliyon

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“…Therefore, if correcting multiple testing is taken into account in the analysis, the most likely finding is the identification of relatively few disease associations, as demonstrated by Smith et al (2011). In the worst-case scenario, correcting for multiple testing in studies with sample sizes leads to the absence of evidence for any disease association, as reported by different studies (Dibble et al, 2020; Herrera et al, 2018; Johnston et al, 2016). In the most optimistic scenario, we can hypothesize that ACE and ACE2 are both genes whose genetic variation and gene expression profiles are at best moderately associated with ME/CFS.…”

Section: Discussionmentioning

confidence: 99%

“…Our analysis focused on three case-control GWAS specifically designed to investigate ME/CFS (Herrera et al, 2018; Schlauch et al, 2016; Smith et al, 2011) (Table 1). There were additional genetic association studies using the UK biobank data, as reviewed elsewhere (Dibble et al, 2020). However, these studies contemplated data from individuals who self-reported a clinical diagnosis of ME/CFS.…”

Section: Methodsmentioning

confidence: 99%

“…In the last two decades, there was explosion of high-throughput technologies allowing to identify a full spectrum of genetic variations, epigenetic changes, and altered gene expressions in patients with complex diseases. Such developments motivated the research community to investigate specific genetic, epigenetic and gene expression signatures in patients with ME/CFS (Almenar-Pérez et al, 2019; Dibble et al, 2020; Kerr, 2008). These investigations generated large amounts of data in which the role of ACE and ACE2 could be specifically assessed.…”

Section: Introductionmentioning

confidence: 99%

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

Malato

Sotzny

Bauer

et al. 2021

Preprint

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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.

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Genetics of COVID‐19 and myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review

Tziastoudi

Cholevas

Stefanidis

et al. 2022

Ann Clin Transl Neurol

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COVID‐19 and ME/CFS present with some similar symptoms, especially physical and mental fatigue. In order to understand the basis of these similarities and the possibility of underlying common genetic components, we performed a systematic review of all published genetic association and cohort studies regarding COVID‐19 and ME/CFS and extracted the genes along with the genetic variants investigated. We then performed gene ontology and pathway analysis of those genes that gave significant results in the individual studies to yield functional annotations of the studied genes using protein analysis through evolutionary relationships (PANTHER) VERSION 17.0 software. Finally, we identified the common genetic components of these two conditions. Seventy‐one studies for COVID‐19 and 26 studies for ME/CFS were included in the systematic review in which the expression of 97 genes for COVID‐19 and 429 genes for ME/CFS were significantly affected. We found that ACE, HLA‐A, HLA‐C, HLA‐DQA1, HLA‐DRB1, and TYK2 are the common genes that gave significant results. The findings of the pathway analysis highlight the contribution of inflammation mediated by chemokine and cytokine signaling pathways, and the T cell activation and Toll receptor signaling pathways. Protein class analysis revealed the contribution of defense/immunity proteins, as well as protein‐modifying enzymes. Our results suggest that the pathogenesis of both syndromes could involve some immune dysfunction.

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Genetic risk factors of ME/CFS: a critical review

Cited by 33 publications

References 61 publications

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

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

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

Genetics of COVID‐19 and myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review

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