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Are CASP8 variants the genetic basis of immune dysfunction in ME/CFS (Citizen Researcher)

kday

Senior Member
Messages
369
After analyzing 23 ME/CFS genomes, I noticed something glaring. There are a few mutations that stuck out like sore thumbs. Likely just risk factors.

But there is a variant in particular (actually a collection of variants, but I'll explain later in the post) that makes me wonder if it could be for the basis for the most common genetic susceptibility to the characteristic immune dysfunction seen in ME/CFS. It's so common that it's in 52% of the ME/CFS genomes looked through. If you add my functionally recovered wife and I, it brings this number up to 56%.

What is it? Oddly, this SNP that is very common in ME/CFS is considered to be protective against breast cancer according to NCBI/NIH's ClinVar database. However, when there is a disease causing variant in this gene, it "leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization."

https://ghr.nlm.nih.gov/gene/CASP8#conditions

The allele frequency for this variant is about 9%, meaning about 9% of the global population carries one or more non-reference alleles. The maximum penetrance is in Europeans (non-Finnish) at around 12.9%. If you go a little narrower and look at North-western Europeans specifically, you find the highest prevalence out of any population: around 13%. The prevalence of this variant is 4x higher in ME/CFS than the population with the highest penetrance! If we dig a little deeper and look at how common homozygous variants are the highest penetrance population (North-western European), you will find that homozygotes are around 8.7/1000 people or 0.87%. In these 23 genomes, 2 were homozygotes which is about 8.7/100 people or 8.7%. If I were to add myself, this number would be higher as I am a homozygote as well. The prevalence of homozygosity in ME/CFS patients 10x larger than the European population of highest penetrance! I'm looking at a small amount of genomes, so you have to consider probability and chance, but I still think this finding is highly intriguing!

What's even more interesting, is that when looking at gnomAD browser, there is strong linkage disequilibrium between rs1045485 and rs34841024. This means when someone inherits one of these CASP8 variants, they will likely inherit the other one as well as the variants are not distributed randomly amongst the population.

These are the variants of interest:
https://gnomad.broadinstitute.org/variant/2-202149589-G-C
https://gnomad.broadinstitute.org/variant/2-202151140-T-G

If you observe the population frequencies for these two variants, the frequencies are practically the same. I highly suggest clicking on the links and looking.

There is a third SNP that may or may not have some linkage disequilibrium (rs35550815). My hypothesis is that if this third SNP doesn't have perfect linkage disequilibrium like the others, this third SNP can form a haplotype that causes susceptibility to Caspase-8 deficiency and the immune abnormalities that come with it (listed above).

This is the third variant:
https://gnomad.broadinstitute.org/variant/2-202150914-A-G

By themselves, these SNPs do not have high CADD scores and prediction models do not predict deleriousness, but I wonder what this haplotype does with this combination of changes in amino acids or if there could be another SNP in the haplotype. Making a computer model prediction for this is out of my scope.

If these findings hold true in higher sample numbers, I do wonder how they could have missed this all these years. Certainly computer models don't predict it to be deleterious. And maybe if someone saw it before, they thought since the classification was a benign variant that protects against breast cancer, it couldn't be part of the pathophysiology and/or a major risk of developing ME/CFS. Perhaps a cognitive bias brought on by the how the variant is labeled. Or maybe my sample size is too small and these findings are by chance.

If not caused by something like chance, I really do believe that it's possible that these variants could be the biggest genetic susceptibility the immune problems associated with ME/CFS. However, researchers need to look into my findings with a larger population size and well-selected cohorts. And if confirmed, they need to look at Caspase-8 function directly.

Methodology. Loaded a bunch of ME/CFS genomes in a database (23 of which had the same variant). There were no "no call" variants out of these 23 individuals. I looked up every CASP8 variant in my Whole Genome Sequence (WGS) file on gnomAD and noticed the linkage disequilibrium described since I have those 3 variants.

I did a couple simple database queries to calculate findings (attached).

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Last edited:
Messages
10
Location
UK
Hi Kday

I ran my Ancestry DNA through your excellent tool and the first item it threw up was homozgous CASP8 rsid1045485 but not the other 2 variants you mention in your post. I am a complete novice on genetics so bear with me please.

Caspace-8 deficiency seems to be linked to a form of ALPs so it is possible that this is an alternative explanation/diagnosis rather than cfs/me?

Dr Bansal here in the UK gave me a "borderline" diagnosis of Cfs/me as I didn't meet all of the criteria. My main symptoms are swollen lymph nodes, swollen liver & spleen, fatigue & muscle weakness all of which made worse the day after exercise. I don't have sleep or cognitive issues. Tests shown elevated IGA rather than a deficiency. Liver biopsy showed granulomas.

Mike