Health Update: Stuck – instead of getting better during an extended stay in Mammoth Lakes, I got worse. Traveling down to the Vegas area did appear to help, perhaps because it’s at a lower elevation.

On the plus side, my autonomic readings (resting heart rate, heart rate variability) have largely stabilized, and my sleep has improved. On the minus side, four months later, though, despite extended periods of rest, my symptoms (nausea, cold sweats) are still pretty easily exacerbated by exertion.

Hopefully time spent at lower elevations will put less pressure on my autonomic nervous system and help.

PrecisionLife, ME/CFS and long COVID

Health Rising has followed PrecisionLife and its work for several years, identifying the biological causes driving subsets in ME/CFS and long COVID and ultimately targeting treatments to them.

PrecisionLife doesn’t simply determine which particular gene variants/mutations are increased/decreased like most genetic tests do. Instead, it identifies sets of gene variants/mutations (gene signatures) that are increased (or decreased), then assesses the biological pathways they interact with, and uses those pathways to identify the mechanisms (enzymes, proteins, specific cell types) that drive them. Next, it searches for repurposed drugs that can impact those mechanisms.

Over the past 11 years, PrecisionLife has done this work for over 60 disease groups. Its work with ME/CFS and long COVID was unique, though: instead of companies or disease groups funding it, it funds all its ME/CFS and long-COVID work.

The Talk

The Splotch!

With its long COVID genetic report, PrecisionLife is embarking on a new venture and I talked with CEO Steve Gardner about it.

But first I had to ask him about the beautiful splotch of colors on the wall behind him. It turned out to be a biological plot of pathways associated with the genetic variants linked to schizophrenia. The colors represent subgroups of patients who have similar drivers of schizophrenia.

This is significant because many, many genetic variants, each of which has a small impact, have been found in schizophrenia, and disentangling them has been difficult. In fact, schizophrenia has been the poster child for frustration in the genetics arena.

If ME/CFS and long COVID are highly polygenic (many, many genes contribute) diseases, schizophrenia is extraordinarily polygenic, yet PrecisionLife has been able to make some sense of that tangled mess, and uncovered a new treatment approach (a statin) that appears to help a subset of patients.

The First Step – A Long-COVID Genetic Report

“This is the first tangible step, if you like, on a much longer and more ambitious journey.” Steven Gardner

PrecisionLife is now offering a long-COVID genetic report. I asked Steve why it’s doing this now, and there were two reasons. For one, PrecisionLife’s ability to validate its long-COVID results using several databases has made it confident of its results.

Second, Steve characterized the report as a first step on the way to achieving a long-term goal: producing validated clinical tests which target subsets of patients who will benefit from a specific therapy.

This new genetic report is not that test, but it allows PrecisionLife to build the infrastructure needed to develop those genetic tests. That includes working with a US firm called Gencove to demonstrate its ability to correctly obtain samples, accurately sequence the DNA, run genetic analyses, use proper quality controls, produce individualized reports, and, finally, securely return them to the participants.

Essentially, they’re building out the operational pipeline they’ll use when they eventually produce clinically validated diagnostic tests.

Educational Report 

Again, this report is not a clinical diagnostic test, and it does not suggest what drugs might help. It’s an educational report that uses PrecisionLife’s sophisticated analyses to potentially offer insights into the genetic roots of a patient’s particular illness.

Steve went to some pains to explain that our genetics represent just one slice – he believes an important slice, but still one slice – of these diseases. They do not explain the totality of these illnesses. Other factors are also in play.

The Report:

1. Helps long-COVID patients understand where they fit in genetically with the rest of the long-COVID community.
2. Helps them identify the mechanistic triggers their particular genetics suggest may be more (or less) in play in their illness.
3. Identifies specific gene variants PrecisionLife believes bear on their condition.
4. Provides curated research materials.
5. Provides wellness tips such as pacing, brain health.

The Six Primary Mechanisms in Long COVID

PrecisionLife’s studies have identified six primary mechanisms it believes are driving long COVID. (The same mechanisms are present in ME/CFS.) It identifies where each person genetically is on the long-COVID continuum. The mechanisms include:

• Immune Regulation
• Cellular Energy Production
• Cognitive Function
• Heart and Blood Vessel Function
• Inflammation and Autoimmunity
• Glucose Processing and Insulin Response.

Why might you want to know where you are, genetically, on these different mechanisms? Steve reported that the different groups that make up long COVID are “very distinctive” genetically. While all or most of these mechanisms may be operating in each patient, PrecisionLife has found that long-COVID patients often demonstrate significantly increased or decreased genetic risk factors in some of them.

You may then be able to identify the mechanisms and genes PrecisionLife’s studies indicate may be impacting your illness.

For example, some individuals’ genetic makeup may put them at reduced risk for immune regulation problems compared to other people with long COVID. Others carry genes that appear to increase their risk of blood vessel problems, inflammation and autoimmunity, or energy production.

PrecisionLife provides the 10 or 20 or so main gene variants you carry which it believes are making a difference in each mechanism. (Honestly, if I did this test, I would plug my genetic variants into several AI search engines and see what it makes of them. :)) It also provides the characteristic symptoms associated with each mechanism.

The most interesting thing about the genetic report for me is the ability to ferret out genetic risk factors that might make one more vulnerable to one of these mechanisms.

Someone whose genetics appeared to put them at higher risk for blood vessel problems, inflammation, or energy production might look into ways to reduce those risks. The reports might prompt some doctors to focus on a specific area and try new things.

Some Thoughts on the Mechanisms

Steve noted that both COVID-19 and EBV infections produce really strong inflammatory factors. If the infection/inflammation doesn’t resolve, immune exhaustion results. Ultimately, this can result in autoimmunity, and PrecisionLife sees a subset of patients with genetic mutations that put them at increased risk of autoimmunity.

PrecisionLife has also identified at least two pathways for brain fog: neuroinflammation and reduced neurotransmitter production. Same symptom – different causes.

Steve also noted that leaky blood vessels in long COVID and ME/CFS may be allowing blood to leak into the surrounding tissues where the microclots may form.

A Deeper Look at the Glucose Processing and the Insulin Response Mechanism

The glucose processing and the insulin response mechanism jumped out at me because: a) the inability to exercise puts everyone more at risk for these problems; and b) metabolic problems are often silent even as they grow.

This area has only recently emerged, but it’s starting to show up in spades. A recent long-COVID overview reported, “Emerging evidence indicates that persistent metabolic abnormalities after COVID-19 may range from transient dysglycaemia to new-onset diabetes mellitus and metabolic syndrome.

Indeed, studies indicate that having a COVID-19 infection increases the risk of getting diabetes by about 40%. (Hospitalization greatly increases the risk. Non-hospitalized COVID-19 patients had about a 15% increased risk of coming down with diabetes over the next year.) This suggests that a COVID-19 infection might nudge the risk upward in a person with metabolic weaknesses. Note that this is full-blown diabetes – something everyone would want to avoid.

Insulin resistance was one area I hoped would not show up in these diseases, yet a seemingly ugly triad (they are all conceivably connected) – chronic inflammation, insulin resistance, and liver disease – popped up in Chris Pontin’s and DecodeME’s large blood-based ME/CFS biomarker study. The researchers reported:

“ME/CFS is thus portrayed by insulin resistance and systemic inflammation, with liver inflammation and dysfunction likely affecting lipid metabolism and the balance between HDL and LDL cholesterol. To our knowledge, the overall combination of blood marker changes we observed does not present in any other disease.”

Across the ME/CFS population as a whole, the DecodeME study found:

• higher triglycerides
• lower HDL cholesterol
• increased triglyceride/HDL ratio
• higher TyG index
• higher HbA1c
• and elevations in ALT, GGT and ALP that can accompany metabolic dysfunction.

The insulin resistance/inflammation/liver findings were the most prominent, but other biomarkers popped out. Lipid and lipoprotein metabolism, which fits nicely with the inflammation findings, was also abnormal, as were complement and oxidative stress.

A large 2024 ME/CFS study found similar results (triglyceride/phosphoglyceride ratio, larger VLDL particles, higher GlycA inflammation signal, and lower HDL-related measures).

It was striking that this particular metabolic component (glucose, inflammation, insulin, liver, lipid metabolism) showed up, given how little focus it’s received over time.

That said, the situation is not dire. It certainly does not mean that most people with long COVID are going to come down with metabolic syndrome or type II diabetes. The changes mostly involved relatively small shifts in laboratory measurements across the entire group.

The fact that physical inactivity did not affect these findings suggested they are part of the disease. That suggests PrecisionLife was on the right track when its data indicated that genetic variants affecting “glucose processing and insulin response” produce one of the six key mechanisms at play in long COVID.

While the changes in laboratory measures were modest, a subgroup likely has more significant issues.

If your PrecisionLife results indicated you have more gene variants affecting “glucose processing and insulin response” than usual, you should probably get more extensive metabolic testing in order to head off these potentially dire consequences.

Peter Attia, MD, has pointed out that metabolic problems are largely “silent” before they become pernicious. Because most doctors don’t do the testing needed to catch them before they become problematic, you can have a growing problem you don’t know about until it gets serious.

If you were to find you were pre-diabetic, you would definitely want to change some things. The consequences of not doing so are too severe.

Attia points out that these metabolic problems heighten the risk of many major diseases, including type II diabetes, heart disease, stroke, high blood pressure, and cancer, and strongly urges that metabolic testing be started early.

Steve reported that PrecisionLife’s work with type II diabetes patients who did well vs those with severe side effects (amputation, blindness, nerve or kidney damage) allowed them to identify 35 severe-disease risk loci, 20 risk-associated genes, 8 druggable targets, and 120 repurposing candidates. They also built a combinatorial risk score (CRS) to predict which complication trajectory an individual patient is more likely to follow.

Educational Guide and Wellness Report

The 81-page Wellness Report provides clear, basic overviews of how the different mechanisms operate and the symptoms each can cause. People who are really up on the disease biology probably will not find much new, but I found having the clear, concise overviews helpful in a disease that can quickly get so complex that it’s easy to miss the forest for the trees.

Twenty pages cover symptoms, why they may occur, the mechanisms they are associated with, and supplements and lifestyle changes that may help.

The next fifteen pages are devoted to short takes on basic lifestyle changes such as deep breathing exercises, fluid intake, managing a crash, symptom tracking, etc.

The last 20 pages describe 13 supplements and the “strength of evidence” for each. It includes the Open Medicine Foundation’s observational TreatME study.

Next for PrecisionLife and ME/CFS, FM, and Long COVID

The ME/CFS, FM, and Long COVID Triage Test

Next up for PrecisionLife is a real mystery beater. Does someone have long COVID or ME/CFS or fibromyalgia? For many patients, the answer might simply reflect which physician they saw. Are they more ME/CFS, or FM, or long COVID-centric?

PrecisionLife believes their testing protocol can distinguish between these diseases. Their data indicate that while ME/CFS and long COVID share mechanisms and overlap significantly, they are distinct enough to be considered separate diseases. The same mechanisms may be operating but, at times, are being produced in different ways.

Precision Life plans to produce a genetic test doctors can order to distinguish which type of patient they have and help them target their treatments more effectively.

The GLP-1 Project

Another project which could benefit ME/CFS, FM, and long-COVID patients is the GLP-1 response project.

PrecisionLife worked with Ovation to identify the genetic signatures associated with strong or weak responses to GLP-1 receptor agonists in 4,600 patients (!). A larger study is underway. Given the dramatically different responses to GLP-1 agonists in these diseases, determining if you’re likely to respond well or poorly (if the results apply to ME/CFS/FM/long COVID) could be very helpful.

Getting the DNA Wellness Report

The Post COVID DNA Wellness report is available at a reduced price ($395) until Oct. 26th when it will go up to $495. It simply requires saliva. Your information will never be shared with anyone other than yourself.

Order it here 

View a sample report here

Health Rising is not participating in PrecisionLife’s affiliate marketing program and does not receive proceeds from the sale of this kit. PrecisionLife may, however, become a corporate sponsor. 

 

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