What DNA Can Teach Us in Understanding POTS, ME/CFS, and Long COVID

Dr Graham Exelby October 2025.

Simplified and condensed from: “Genomic Redundancy as a Driver of Chronicity in POTS and Long COVID”

Introduction

Conditions like Postural Orthostatic Tachycardia Syndrome (POTS), Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and Long COVID affect many people with symptoms such as dizziness, fatigue, brain fog, palpitations, and post-exertional malaise (PEM, where even mild activity leads to a crash in energy). These conditions can be difficult to diagnose and treat because they are not caused by a single gene or organ problem—instead, they often stem from subtle vulnerabilities in the body's interconnected systems.

Recent research suggests that these illnesses may be better understood as the result of multiple weak points in our body’s pathways—the networks that control immunity, metabolism, circulation, and energy. Think of these pathways like a chain: one weak link might not break it, but several overlapping ones can make the whole system fragile, especially after a trigger like an infection, trauma, or vaccination. When these weak points overlap (called "redundancy"), symptoms can become persistent and hard to resolve.

Why DNA May Matter

DNA analysis looks at small genetic variations called single nucleotide polymorphisms (SNPs). These aren't "bad genes" that guarantee illness, but they can influence how efficiently pathways work. A single SNP is rarely enough to cause problems, but when several cluster in related pathways, they can reduce the body's resilience, making someone more vulnerable to chronic symptoms.

• For patients: DNA can help explain why symptoms persist even when standard tests (like pathology or imaging) look “normal.” It provides a personalized map of potential vulnerabilities.

• For management: Knowing the pathways involved allows targeted treatments—e.g., supplements to support a sluggish recycling process (methylation), diet changes to reduce inflammation, or medications to stabilize overactive immune responses.

• For families: DNA analysis can highlight shared vulnerabilities among relatives. This doesn't mean illness is inevitable, but it can guide prevention, such as tailored diets, lifestyle adjustments, or earlier screening for related risks like cardiovascular issues or certain cancers.

DNA testing goes beyond conventional family history by revealing hidden pathway weaknesses that might not show up in family stories alone. For example, family history might note "aunt had fatigue," but DNA can pinpoint if that's linked to specific methylation or immune variants, allowing proactive steps.

What the Study Found

In a preliminary analysis of small patient groups with POTS, ME/CFS, Long COVID, vaccine reactions, and some with cancer, eight pathways kept appearing as common vulnerabilities. These were identified through SNP-based DNA testing and matched to clinical symptoms, lab results, and imaging:

1. Immune activation (how the body senses and responds to "danger" signals like infections or inflammation—think of it as an over-sensitive alarm system).

2. Methylation and repair (the body's recycling system for chemicals like homocysteine; if inefficient, it can lead to buildup causing fatigue, inflammation, or DNA damage).

3. Mast-cell regulation (how we process histamine, the chemical behind allergic reactions; poor regulation can cause flushing, dizziness, or "allergy-like" flares without true allergies).

4. Oxidative stress (how well we neutralize free radicals, harmful molecules from energy production; weak defences can damage cells, especially in mitochondria, the cell's power plants).

5. Tryptophan/kynurenine metabolism (balancing serotonin for mood vs. toxic by-products; imbalances can lead to brain fog or excitotoxicity, where nerves get overstimulated).

6. Hormone and stress pathways (COMT) (how we clear adrenaline and oestrogen; "slow" variants might heighten anxiety, while "fast" ones could cause dopamine dips leading to fatigue).

7. APOE and lipid handling (how the brain and blood vessels repair themselves; APOE4 variants, for example, can increase vulnerability to cognitive issues or poor healing).

8. Structural/vascular load (tissue and vein strength; weaknesses here can cause "preload failure," where blood doesn't return efficiently to the heart on standing, like a pump low on fluid).

Different conditions had different “weights” or emphases:

• POTS: Mostly mechanical preload failure and mast-cell issues, leading to orthostatic symptoms like rapid heartbeat on standing.

• ME/CFS: Mainly methylation problems and toxic by-products from tryptophan metabolism, explaining severe PEM and energy crashes.

• Long COVID: Multiple pathways overlapping, creating redundancy that makes recovery difficult.

• Vaccine reactions: A “triad” of immune, methylation, and mast-cell dysfunction, often triggered by the vaccine's immune stimulation.

• Hybrids (infection + vaccine): Broad redundancy across most pathways—the hardest to treat.

• Cancer overlaps: Methylation and repair pathways combined with immune amplification, suggesting shared vulnerabilities (though this is preliminary and needs more research).

Why Redundancy Matters

The key insight is that redundancy—multiple weak pathways together—predicts who becomes chronically unwell. A person with one weak pathway might recover quickly after a virus, while someone with four or five could develop persistent symptoms. This explains variability within families: one sibling recovers from COVID, another gets Long COVID, due to differing "weak point loads" in their DNA.

Family history is a good starting point (e.g., noting patterns of fatigue or autoimmune issues), but DNA testing reveals the "why" behind those patterns—specific pathways that can be targeted early, even before symptoms fully emerge.

Practical Use for Patients and Families

1. Guiding Treatment Tailor interventions based on pathways:

   • Methylation problems → Test homocysteine levels; consider B12, or phospholipids (part of a complex management plan).

   • Mast-cell problems → Low-histamine diet, antihistamines (H1/H2 blockers), or mast-cell stabilizers like cromolyn.

   • Oxidative stress → Antioxidants like CoQ10, alpha-lipoic acid (ALA), or NAD+ precursors (e.g., nicotinamide riboside).

   • Structural load → Posture therapy, compression garments, lymphatic drainage, or vascular imaging (e.g., Doppler ultrasound).

2. Monitoring Risk Families can watch for vulnerabilities:

   • COMT variants may mean more anxiety or fatigue under stress—suggest stress management early.

   • APOE4 variants may raise risks for cognitive decline or neurodegeneration—prompt brain-healthy habits like exercise and omega-3s.

   • Methylation fragility may increase cardiovascular or cancer risks—encourage earlier screenings (e.g., mammograms or blood tests) beyond standard family history guidelines.

3. Personalized Prevention 

   • Diet: Nutrient-rich, anti-inflammatory; tailor to needs (e.g., low-histamine if mast-cell issues).

   • Lifestyle: Prioritize sleep, gentle exercise, and reducing toxins.

   • Early supplementation: Where DNA shows gaps, but only under medical guidance to avoid interactions.

Guidance for Healthcare Providers (e.g., GPs)

This section provides practical info to help GPs decide when and how to recommend DNA testing, especially when it adds value over conventional family history.

• Who Needs DNA Testing? DNA testing is most useful when family history alone doesn't explain symptoms or risks. Consider it for:

  • Patients with unexplained chronic symptoms (e.g., persistent fatigue, orthostatic issues) despite normal tests—testing can reveal pathway clusters guiding targeted therapies.

  • Familial patterns of similar conditions (e.g., multiple relatives with fatigue or dysautonomia), to identify shared SNPs beyond anecdotal history.

  • High-risk scenarios: Post-viral/vaccine persistence, or overlaps with autoimmunity/cancer, where early pathway insights could prevent escalation.

  • Prevention in asymptomatic relatives: If a patient's DNA shows redundancy (e.g., methylation + immune variants), test family members for proactive management. Avoid routine testing for everyone; it's best when symptoms are refractory or family history suggests polygenic factors (as per studies like DecodeME GWAS, 2025).

    
    

• Types of Testing Direct-to-consumer options (e.g., 23andMe, Ancestry) are affordable but limited—they often miss comprehensive SNP coverage for these pathways and lack clinical interpretation. For deeper analysis, recommend advanced clinical-grade tests (e.g., SNP arrays with >600,000 markers, such as used by molecular biologist Dr Valerio Vittone whose DNA testing provided the backbone for this document). These are more expensive but provide pathway-focused reports, including redundancy scoring.  Understanding and interpretation of results is critical in providing the accuracy needed in management advice.

  
  

• How to Access and Interpret 

  • Order through labs offering SNP genotyping with pathway annotation, or via Dr Vittone’s website- https://www.drvaleriovittone.com/.

  • Interpretation: Focus on clusters, not isolated SNPs—e.g., multiple methylation variants (MTHFR + MTRR) are more meaningful than one.

  • Follow-up: Integrate with clinical data (e.g., homocysteine labs for methylation). Discuss results in context to avoid over-alarming patients.

    
    

• Limitations and Caveats 

  • Preliminary evidence: Based on small studies; not yet in standard guidelines (e.g., NICE for ME/CFS or NIH for Long COVID).

  • Not deterministic: Variants indicate vulnerability, not destiny.

  • Ethical notes: Ensure informed consent; results may cause anxiety. Refer to resources like the Bateman Horne Center Clinical Care Guide (2025) or ME Association for balanced advice.

Conclusion

This study is preliminary and based on small patient numbers, so findings must be interpreted with caution. But it highlights an important direction: these illnesses are not random or purely functional—they reflect overlapping weaknesses in our body’s pathways.

DNA analysis, when carefully interpreted, can:

• Explain why illness develops.

• Guide personalized treatment.

• Offer reassurance or preventive strategies for families, going beyond family history by pinpointing actionable pathways.

The long-term vision is that by understanding pathway vulnerabilities early, we can move medicine from reacting after illness develops to anticipating and preventing disease before it takes hold. For more, see resources like the DecodeME study (medrxiv.org) or Chambers' review on MTHFR links (isom.ca). Consult your GP for personalized advice.