From Genomic Redundancy to Physiological Network Fragility:A Systems-Level Model of Chronicity in POTS, Long COVID, and Related Neuroimmune Disorders

Dr Graham Exelby (2026)

Systems-Level Insights Derived from Genomic Studies in POTS and Long COVID (2022–2026) with Dr Valerio Vittone

Abstract

Background

POTS, Long COVID, ME/CFS, vaccine-associated syndromes, and connective tissue-associated neuroimmune disorders are traditionally approached as distinct clinical entities. However, increasing overlap in autonomic dysfunction, neurovascular abnormalities, inflammatory activation, connective tissue signatures, oxidative stress, and metabolic dysfunction suggests the presence of shared systems-level pathophysiology rather than isolated disease processes. (1–6)

Methods

This exploratory systems-level study integrated SNP pathway analysis with detailed clinical phenotyping, autonomic assessment, amino acid profiling, haemodynamic testing, and multimodal neurovascular imaging across clinically characterised cohorts. Variants were grouped into interacting physiological domains including innate immune signalling, oxidative stress regulation, connective tissue integrity, methylation pathways, mitochondrial metabolism, mast-cell regulation, lipid handling, and neurovascular stability.

Results

A recurrent pattern of cumulative genomic redundancy was identified across cohorts, characterised by convergence of multiple low-penetrance variants within interacting biological pathways. Clinical persistence correlated more strongly with multi-axis pathway convergence than with isolated variants alone. The RAGE–TLR4–NLRP3–STAT3 inflammatory amplifier network emerged as a central recurrent pathway linking inflammatory persistence, oxidative stress, neurovascular dysfunction, connective tissue instability, mitochondrial impairment, and impaired adaptive reserve. (7–24) Structural pathway redundancy involving connective tissue and extracellular matrix regulation was strongly associated with preload instability, venous compliance abnormalities, orthostatic intolerance, and impaired neurovascular compensation. Across cohorts, increasing redundancy burden correlated with progressive physiological network fragility, impaired recovery capacity, and chronic multisystem instability.

Conclusion

These findings support a model in which POTS, Long COVID, ME/CFS, and related disorders represent differing clinical expressions of physiological network fragility arising from convergent pathway disruption. Cumulative genomic redundancy may progressively erode adaptive reserve across interconnected neuroimmune–vascular–metabolic systems, predisposing susceptible individuals to persistent maladaptive states following infectious, inflammatory, hypoxic, mechanical, endocrine, or toxic stressors. This framework supports transition toward pathway-informed and anticipatory systems medicine.

Full paper link-

From Genomic Redundancy to Physiological Network Fragility.pdf

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