Hypothesis The Potential Role of Ocular and Otolaryngological Mucus Proteins in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, 2023, Craddock et al

[Tom Kindlon]

The Potential Role of Ocular & Otolaryngological Mucus Proteins in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

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https://www.researchsquare.com/article/rs-3171709/v1

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness associated with a constellation of other symptoms.

While the most common symptom is unrelenting fatigue, many individuals also report suffering from rhinitis, dry eyes and a sore throat.

Mucin proteins are responsible for contributing to the formation of mucosal membranes throughout the body.

These mucosal pathways contribute to the body’s defense mechanisms involving pathogenic onset.

When compromised by pathogens the epithelium releases numerous cytokines and enters a prolonged state of inflammation to eradicate any particular infection.

Based on genetic analysis, and computational theory and modeling we hypothesize that mucin protein dysfunction may contribute to ME/CFS symptoms due to the inability to form adequate mucosal layers throughout the body, especially in the ocular and otolaryngological pathways leading to low grade chronic inflammation and the exacerbation of symptoms.


INIM Webinar from 2020 on this:
Travis Craddock, Ph.D.: The Potential Role of Ocular and Otolaryngological Mucus Proteins in ME/CFS

 

[Hoopoe]

I'm skeptical about this for various reasons.

The control group was the 1000 Genomes Project, which used different and more reliable technology than 23andme which provided the data for participants. 23andme tends to falsely report rare SNPs in people that do not really have them.

Also I vaguely remember that mucins and similar genes with barrier or immune function are highly polymorphic, which seems like it might make false positives more likely in some situations, although I can't think clearly enough at the moment to figure out if that would be a problem in this study or not. The use of CADD scores to assess pathogenicity of mutations could be questionable if these mucins are indeed highly polymorphic.

The paper is still in peer review. I wonder what the reviewer will say.

PS: I got confused because the authors report the allele frequency as percentage according to the table header, so I interpreted 0.8 to mean 0.8% while this seems to be an error. All the SNPs that initially looked like uncommon/rare ones are actually fairly common, so the criticism of 23andme's false positives for rare SNPs seems irrelevant.

 

[Hoopoe]

The same mistake was made in a previous study:

It is tempting to mine the abundance of DNA data that is now available from direct-to-consumer genetic tests but this approach also has its pitfalls A recent study put forth a list of 50 single nucleotide polymorphisms (SNPs) that predispose to Chronic Fatigue Syndrome (CFS), a potentially major advance in understanding this still mysterious condition. However, only the patient cohort data came from a commercial company (23andMe) while the control was from a genetic database. The extent to which 23andMe data agree with genetic reference databases is unknown. We reanalyzed the 50 purported CFS SNPs by comparing to control data specifically from 23andMe which are available through public platform OpenSNP. In addition, large high-quality database ALFA was used as an additional control. The analysis lead to dramatic change with the top of the leaderboard for CFS risk reduced and reversed from an astronomical 129,000 times to 0.8. Errors were found both within 23andMe data and the original study-reported Kaviar database control. Only 3 of 50 SNPs survived initial study criterion of at least twice as prevalent in patients, EFCAB4B, involved in calcium ion channel activation, LINC01171, and MORN2 genes. We conclude that the reported top-50 deleterious polymorphisms for Chronic Fatigue Syndrome were more likely the top-50 errors in the 23andMe and Kaviar databases. In general, however, correlation of 23andMe control with ALFA was a respectable 0.93, suggesting an overall usefulness of 23andMe results for research purposes but only if caution is taken with chips and SNPs.

https://www.medrxiv.org/content/10.1101/2020.10.27.20220939v2.full

 

[Hoopoe]

I was curious and picked rs9262549 to examine more closely because it had the highest reported difference between cases and controls. I was looking at the table where it is listed in the study.

The dbSNP database reported alelle frequencies for the reference of G=0.1915, and the alternate of C=0.8085 for rs9262549 (looking at the 1000 Genomes data as in this study).

The authors are reporting a missense S>T mutation (at amino acid level). This corresponds to a G>C change at DNA level which matches what dnSNP says.

Here's where things get unclear for me. They appear to be reporting a G>C change in 0.72 of the case alleles versus 0.19 of the control alleles. To me it looks like the 0.19 is an error and that it should be 0.80, because 0.19 is the frequency of G, not of C.

Or maybe what they mean is that the reference allele is more frequent in patients than controls and this is just the weird way this is represented by the software they used.

PS: but even if this is just a weird way to represent a difference between controls, it does not look promising because a look at dbSNP shows that an allele frequency of 0.72 is close to what one would expect in a population of European origin. On dbSNP the Allele Frequency Aggregator European database with 20336 samples shows values of G=0.27734 C=0.72266. So this difference could simply be due to combination of the study participants being primarily of European descent, and the use of a suboptimal control group.

 

[Andy]

Now published.

The potential role of ocular and otolaryngological mucus proteins in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness associated with a constellation of other symptoms. While the most common symptom is unrelenting fatigue, many individuals also report suffering from rhinitis, dry eyes and a sore throat. Mucin proteins are responsible for contributing to the formation of mucosal membranes throughout the body. These mucosal pathways contribute to the body’s defense mechanisms involving pathogenic onset. When compromised by pathogens the epithelium releases numerous cytokines and enters a prolonged state of inflammation to eradicate any particular infection. Based on genetic analysis, and computational theory and modeling we hypothesize that mucin protein dysfunction may contribute to ME/CFS symptoms due to the inability to form adequate mucosal layers throughout the body, especially in the ocular and otolaryngological pathways leading to low grade chronic inflammation and the exacerbation of symptoms.

Open access, https://molmed.biomedcentral.com/articles/10.1186/s10020-023-00766-8

 

[Sean]

...inability to form adequate mucosal layers throughout the body...

Might be something to this, given frequent reports of dry eyes and mouth, etc.