Heparan Sulfate as a Convergence Interface for Polygenic Control-Layer Erosion in Myalgic Encephalomyelitis

1.1 Myalgic Encephalomyelitis as a disorder of control rather than capacity

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is characterized by post-exertional malaise (PEM), a delayed and disproportionate worsening of symptoms following physical, cognitive, or orthostatic stress. PEM often occurs in the absence of overt exertion, inflammatory markers, or structural pathology, and can be triggered by everyday physiological demands such as standing, heat exposure, or sustained cognitive load. These features have proven difficult to reconcile with models focused solely on reduced energetic capacity, mitochondrial dysfunction, or persistent inflammation.

An alternative framing is that ME/CFS reflects a disorder of physiological control and recovery, rather than baseline capacity. In this view, the defining abnormality is not an inability to perform work per se, but an impaired ability to interpret, buffer, and resolve physiological stress signals over time. This framing is supported by several consistent observations: normal or near-normal resting laboratory values; delayed rather than immediate symptom exacerbation; large variability in tolerance across days; and symptom amplification that is often uncoupled from the absolute magnitude of exertion.

Within this context, PEM can be conceptualized as a failure of stress-signal resolution, in which normal physiological inputs precipitate delayed, multi-system dysfunction due to impaired regulatory precision. Identifying where such control failure arises, and how genetic susceptibility contributes to it, remains a central challenge in ME/CFS research.

1.2 Polygenic signals without single causal loci

Genetic studies of ME/CFS have consistently failed to identify single high-penetrance causal variants. Instead, emerging evidence from metabolite-linked genome-wide association studies (mGWAS) and combinatorial genetic analyses points toward distributed, small-effect genetic contributions that influence immune regulation, lipid metabolism, endoplasmic reticulum (ER) stress handling, and vascular or endothelial biology.

This pattern suggests that genetic risk in ME/CFS may operate primarily by lowering system-level robustness, rather than by directly initiating pathology. In such a framework, disease susceptibility arises when multiple control layers—immune signaling duration, protein quality control, membrane composition, and vascular regulation—are rendered fragile. Environmental stressors such as infection, inflammation, or oxidative stress may then push the system into a persistent dysfunctional state.

However, linking these polygenic signals to a specific physiological failure mode has remained challenging. In particular, there is a gap between genetic enrichment for immune, metabolic, and vascular processes and the defining clinical phenomenon of PEM. A unifying interface is needed—one that can plausibly integrate upstream genetic vulnerability with downstream, shear-sensitive symptom triggering.

2.1 The endothelial glycocalyx as a mechanosensory system

The vascular endothelium is continuously exposed to shear stress generated by blood flow. Rather than responding passively, endothelial cells actively sense and transduce shear forces into intracellular signals that regulate vascular tone, permeability, and perfusion distribution. A central component of this mechanosensory apparatus is the endothelial glycocalyx, a carbohydrate-rich layer composed primarily of proteoglycans and glycosaminoglycans, including heparan sulfate (HS) (Florian et al., 2003; Weinbaum, Tarbell & Damiano, 2007).

Heparan sulfate chains, attached to transmembrane and glycosylphosphatidylinositol-anchored proteoglycans, play a critical role in detecting changes in flow and transmitting this information to intracellular signaling complexes. Experimental studies have shown that disruption of HS alters endothelial responses to shear stress, including impaired activation and spatial localization of endothelial nitric oxide synthase (eNOS). Importantly, this effect reflects a loss of signal precision—that is, altered timing and localization of nitric oxide (NO) signaling—rather than a simple reduction in NO production (Florian et al., 2003; Pahakis et al., 2007; Higashi et al., 2014).

Through this mechanism, the glycocalyx functions as a shear-signal filter, converting mechanical inputs into appropriately scaled and localized biochemical responses. When intact, this system allows normal fluctuations in flow to be accommodated without injury. When compromised, identical shear forces may be misinterpreted, leading to heterogeneous perfusion, endothelial stress, and downstream tissue effects (Tarbell & Cancel, 2016).

2.2 Heparan sulfate as a precision interface rather than a primary driver

While HS is essential for normal endothelial mechanosensing, it is not an autonomous driver of pathology. Glycocalyx integrity is highly sensitive to inflammatory signaling, oxidative stress, ER stress, and alterations in membrane composition. Under such conditions, HS chains may be shortened, shed, or improperly processed, reducing mechanosensory fidelity (Reitsma et al., 2007; Tarbell & Cancel, 2016).

Crucially, this places HS at the level of a convergence interface rather than a primary disease initiator. Genetic variants that impair immune signal termination, protein quality control, lipid handling, or membrane stability do not directly disrupt HS biosynthesis, but they create an environment in which glycocalyx maintenance and recovery are compromised. In this setting, HS dysfunction emerges secondarily, as a consequence of upstream control-layer fragility.

This distinction has important implications for understanding PEM. Impaired HS-dependent shear sensing would be expected to convert otherwise normal physiological shear—arising from standing, mild exertion, or cognitive stress—into maladaptive endothelial signaling. Because such signaling errors propagate through vascular and metabolic systems over time, symptom exacerbation would be delayed rather than immediate. Moreover, transient improvements in glycocalyx function could temporarily mask warning signals without restoring upstream control, leading to a false sense of capacity followed by a larger delayed crash (Tarbell & Cancel, 2016).

Accordingly, HS is best understood not as a singular genetic cause of ME/CFS, but as a vulnerable precision layer through which polygenic control-layer erosion manifests as shear-triggered, delayed multi-system dysfunction. This framing provides a biologically plausible bridge between distributed genetic susceptibility and the defining clinical features of PEM.

3.1 Overview of the metabolite-linked mGWAS study

Recent metabolite-informed genome-wide association analysis provides an important, hypothesis-free window into genetic contributors to ME/CFS. In Exploring a genetic basis for the metabolic perturbations in ME/CFS, a conditional meta-GWAS approach was used to decompose complex metabolic signatures into genetically associated components. This analysis identified 27 significant single-nucleotide polymorphisms mapping to 15 genes, with multiple loci converging on pathways related to immune regulation, lipid metabolism, membrane composition, and cellular stress handling (Huang et al., 2026).

Notably, the identified genes were not unified by a single biochemical pathway or disease mechanism. Instead, they spanned multiple regulatory domains that influence how physiological stress is processed, distributed, and resolved. This pattern is consistent with a polygenic architecture in which disease susceptibility reflects reduced robustness across interacting control layers, rather than direct disruption of a single molecular function.

3.2 Definition of the shared genetic scope (Table 1)

For the purposes of the present analysis, we restricted genetic scope to a conservative intersection between the mGWAS-identified genes and an independently curated genetic framework focused on immune, metabolic, vascular, and recovery-related control processes. This yielded a set of ten genes explicitly present in both sources, forming the basis of Table 1: NLRC5, TMEM258, HERPUD1, MYRF, CETP, LIPC, LIPG, APOE, SCGN, and CPS1.

These genes span multiple functional domains: Immune signal regulation and persistence (e.g., NLRC5), Endoplasmic reticulum stress resolution and glycoprotein processing (TMEM258, HERPUD1), Membrane lipid composition and stability (MYRF, CETP, LIPC, LIPG, APOE), Neuroendocrine execution gain (SCGN), Metabolic recovery and clearance capacity (CPS1).

Importantly, none of these genes encode enzymes directly responsible for heparan sulfate biosynthesis, sulfation, or degradation. This absence argues against heparan sulfate dysfunction arising as a primary genetic lesion in ME/CFS. Instead, these genes collectively define an upstream biological context in which cellular stress handling, membrane integrity, immune signal termination, and recovery bandwidth are compromised (Huang et al., 2026).

3.3 Implications for heparan-sulfate vulnerability

Although heparan sulfate is not directly encoded by the genes in Table 1, its maintenance and functional integrity depend critically on the processes these genes regulate. Proper synthesis, presentation, and recovery of endothelial heparan sulfate proteoglycans require intact ER quality control, stable membrane platforms, balanced lipid composition, and tightly regulated immune signaling. Disruption in any of these domains increases susceptibility to glycocalyx thinning, altered sulfation patterns, or impaired post-stress restoration.

Thus, the shared genetic signal identified in Table 1 is best interpreted as conferring trait-level vulnerability of endothelial control surfaces, rather than specifying a discrete pathogenic pathway. Within such a vulnerable state, heparan sulfate–dependent shear sensing becomes a plausible downstream failure point through which polygenic control-layer erosion is expressed physiologically.

This framing provides a mechanistic bridge between distributed genetic susceptibility and the delayed, shear-sensitive symptom exacerbation characteristic of post-exertional malaise. The following section extends this interpretation by examining whether an independent combinatorial genetic analysis converges on a similar biological environment, with particular attention to processes directly relevant to glycosaminoglycan biology and endothelial mechanosensing.

Table 1. Shared metabolite-linked genes (mGWAS) supporting control-layer vulnerability

Note: keep this table aligned with your finalized Table 1 (no content rewriting here).

4.1 Rationale for incorporating combinatorial genetics

While metabolite-linked mGWAS provides a conservative and interpretable view of genetic susceptibility in ME/CFS, its power is limited by single-variant association thresholds. To assess whether the biological environment implicated by Table 1 is independently supported, we examined results from a complementary combinatorial genetic analysis performed by PrecisionLife (PrecisionLife Ltd., 2025).

PrecisionLife applies a high-order combinatorial approach to identify networks of interacting variants that collectively associate with disease, rather than prioritizing individual loci. This methodology is particularly well suited to conditions such as ME/CFS, where genetic risk is distributed across multiple interacting pathways and where single-variant effects are modest. Importantly, the PrecisionLife analysis was conducted independently, using a distinct cohort and analytical framework, thereby providing an opportunity for external validation at the level of biological function rather than gene identity (PrecisionLife Ltd., 2025).

4.2 Functional enrichment identified by PrecisionLife

The PrecisionLife preprint reports enrichment across several biological domains that closely mirror the control-layer vulnerabilities identified in the metabolite-linked mGWAS study. Specifically, combinatorial gene networks were enriched for: Immune regulation, particularly genes involved in immune–endothelial interaction and interferon-adjacent control rather than cytokine production, Endoplasmic reticulum stress and protein quality control, including chaperones and glycoprotein-folding machinery, Glycosaminoglycan and proteoglycan biology, encompassing enzymes involved in glycan chain initiation and modification, Extracellular matrix organization, lipid transport, and endothelial coupling, together defining the structural and metabolic environment that conditions vascular mechanosensing under shear stress. .

Notably, this enrichment pattern does not center on classical inflammatory mediators or mitochondrial genes. Instead, it highlights systems that regulate cell-surface structure, signal fidelity, and stress recovery, consistent with a model of impaired physiological control rather than primary energetic failure (PrecisionLife Ltd., 2025; Huang et al., 2026).

4.3 PrecisionLife genes supporting heparan-sulfate–relevant biology (Table 2)

To maintain interpretive restraint, we did not attempt to reproduce or exhaustively catalog all PrecisionLife candidate genes. Instead, we curated a limited subset of genes whose known biological roles plausibly support heparan-sulfate–dependent endothelial mechanosensing, either directly or through upstream processes that condition glycocalyx stability (PrecisionLife Ltd., 2025).

This curated set is presented in Table 2. The included genes fall into four functional categories: Direct glycosaminoglycan and proteoglycan biology, including enzymes required for initiation and structural modification of glycosaminoglycan chains (e.g., XYLT1, GCNT1), ER glycoprotein quality control, which constrains the synthesis and recovery of proteoglycan core proteins under stress (e.g., UGGT1), Extracellular matrix and structural coupling, which anchors endothelial glycocalyx components and modulates mechanotransduction under shear (e.g., COL4A4, COL19A1, COLEC12), Immune and lipid-endothelial modulators, which shape the inflammatory and membrane environment that determines glycocalyx vulnerability and recovery (e.g., TRIM26/31, ABCA1, ANGPT1).

Crucially, Table 2 does not assert that these genes are causal for ME/CFS, nor does it imply that heparan sulfate dysfunction arises from direct genetic defects in HS biosynthesis. Rather, it demonstrates that an independent combinatorial analysis converges on biological systems known to regulate glycocalyx integrity, shear-signal precision, and endothelial stress handling (PrecisionLife Ltd., 2025).

4.4 Interpretation: convergence without gene inflation

Taken together, the PrecisionLife findings provide independent support for the biological environment inferred from Table 1. Although direct gene-level overlap between datasets is limited—as expected given methodological differences—both analyses converge on: immune signal regulation rather than hyperinflammation, ER stress resolution and protein quality control, lipid and membrane organization, extracellular matrix and glycosaminoglycan-dependent endothelial function (PrecisionLife Ltd., 2025; Huang et al., 2026).

This convergence strengthens the interpretation that heparan sulfate–dependent shear sensing represents a downstream precision interface through which polygenic control-layer fragility may manifest clinically. PrecisionLife thus serves not as a second source of candidate genes, but as an orthogonal validation of the functional context in which endothelial mechanosensing failure becomes likely (PrecisionLife Ltd., 2025).

The following section integrates these genetic findings into a unified mechanistic model linking polygenic control-layer erosion, heparan-sulfate vulnerability, and the delayed, shear-activated symptom exacerbation characteristic of post-exertional malaise.

Table 2. PrecisionLife genes supporting HS-relevant biology (functional convergence)

PrecisionLife candidate genes were conservatively selected based on established roles in glycosaminoglycan biology, ER quality control, immune-mediated endothelial stress, or extracellular matrix–lipid coupling. Inclusion does not imply causation.

Interpretation: Table 2 demonstrates functional convergence on glycosaminoglycan biology, ER quality control, immune–endothelial stress, and ECM–lipid coupling, rather than direct gene-level overlap with the metabolite-linked mGWAS.

5.1 Heparan sulfate and endothelial shear sensing

Heparan sulfate (HS), as a core component of the endothelial glycocalyx, plays a critical role in translating blood-flow–derived shear stress into spatially and temporally precise endothelial signaling. Rather than acting as a passive structural coating, HS-bearing proteoglycans (e.g., glypicans and syndecans) participate directly in mechanotransduction, shaping the localization, timing, and duration of endothelial nitric oxide synthase (eNOS) activation during changes in flow (Florian et al., 2003; Weinbaum, Tarbell & Damiano, 2007; Tarbell & Cancel, 2016).

Experimental and physiological studies consistently show that intact HS is required for normal flow-induced nitric oxide (NO) signaling, endothelial alignment, and adaptive vasoreactivity. When HS integrity is compromised—through enzymatic cleavage, oxidative damage, or impaired biosynthesis—shear stress is no longer processed as regulatory information. Instead, flow changes produce heterogeneous, poorly localized endothelial responses characterized by mistimed NO release and microvascular instability (Florian et al., 2003; Pahakis et al., 2007; Tarbell & Cancel, 2016; Higashi et al., 2014).

This distinction is central to the present framework: PEM is not modeled as a failure of NO production per se, but as a failure of NO precision under shear. HS sits precisely at this control point (Tarbell & Cancel, 2016).

5.2 Downstream erosion versus trait-level vulnerability

HS dysfunction can arise through two non-exclusive mechanisms, which align with the broader control-layer architecture proposed in this paper.

State-dependent (downstream) erosion.
The endothelial glycocalyx is highly sensitive to inflammatory signaling, reactive oxygen species (ROS), ischemia–reperfusion, and enzymatic degradation by heparanase. Acute infections and inflammatory stressors—well-recognized triggers in ME/CFS—are known to induce rapid HS shedding, leading to increased endothelial permeability, altered mechanosensing, and impaired flow adaptation. In this mode, HS loss functions as a damage amplifier, exacerbating shear sensitivity once disease processes are active (Reitsma et al., 2007; Tarbell & Cancel, 2016).

Trait-like (upstream) vulnerability.
Separately, HS structure and function are determined by a coordinated network of genes governing proteoglycan core protein processing, glycosaminoglycan chain initiation, glycan branching, sulfation patterns, and ER quality control. Mild genetic variation across these pathways—well below thresholds causing overt connective tissue or developmental disorders—could plausibly reduce baseline glycocalyx fidelity. Such variation would not cause disease in isolation but could lower the safety margin for endothelial shear handling, rendering normal physiological stressors more likely to trigger downstream instability (Xu & Esko, 2014; Weinbaum, Tarbell & Damiano, 2007).

This dual framing avoids a false dichotomy: HS dysfunction can be both a downstream consequence of inflammatory stress and an upstream vulnerability layer that increases the probability of control failure.

5.3 Genetic convergence on the HS–shear–NO interface

The two independent genetic datasets considered in this paper converge on biological domains that directly shape HS integrity and its mechanosensory environment.

The metabolite-linked mGWAS study (Exploring a genetic basis in ME) identifies genes spanning immune control (e.g., NLRC5), ER stress and protein quality control (TMEM258, HERPUD1), membrane and lipid stability (MYRF, CETP, LIPC, LIPG), vascular buffering (APOE), neuroendocrine execution gain (SCGN), and recovery bandwidth (CPS1). While these genes do not encode HS biosynthesis enzymes directly, they define the cellular environment that governs proteoglycan processing, membrane stability, and endothelial stress tolerance (Huang et al., 2026).

Independently, the PrecisionLife combinatorial analysis identifies enrichment across immune regulation, ER stress and proteostasis, lipid–ECM coupling, and—critically—glycosaminoglycan biology. Within its candidate gene set are direct anchors for HS involvement (e.g., XYLT1, initiating proteoglycan glycosaminoglycan chain synthesis; GCNT1, regulating glycan branching; UGGT1, governing ER quality control of glycoproteins), along with ECM scaffolding and endothelial interface genes (COL4A4, COL19A1, COLEC12) and immune regulators capable of driving glycocalyx erosion under stress (PrecisionLife Ltd., 2025).

Taken together, these datasets support a coherent interpretation: ME/CFS-associated genetic risk does not point to a single defective pathway, but to polygenic erosion of control layers that converge at the endothelial surface, where HS defines the fidelity of shear sensing and NO timing (Huang et al., 2026; PrecisionLife Ltd., 2025).

5.4 HS dysfunction as a trigger amplifier for PEM

Within this framework, HS loss or distortion does not initiate disease, but it meaningfully shapes how and when PEM is triggered. Reduced HS integrity increases microvascular flow heterogeneity and converts otherwise normal shear stress—arising from standing, walking, thermal stress, or cognitive demand—into a mechanical stressor. This shear-activated failure state exposes underlying vulnerabilities in immune signal termination, membrane stability, and recovery capacity (Tarbell & Cancel, 2016).

Importantly, this model also predicts a clinically relevant paradox: partial restoration or support of HS-dependent shear sensing in an otherwise unstable system may transiently reduce symptoms and create a subjective sense of increased capacity, without restoring true control headroom. Increased activity during this window could then amplify cumulative shear and oxidative stress, resulting in a delayed and more severe crash.

5.5 Integrative interpretation

Heparan sulfate is best understood not as a new primary lesion in ME/CFS, but as a precision buffer at the endothelial control surface. Genetic variation across immune regulation, ER quality control, lipid handling, and ECM coupling can weaken the environment required for HS maintenance. Acute inflammatory or oxidative insults can then erode HS directly, tipping the system into a state where shear stress becomes injurious (Reitsma et al., 2007; Tarbell & Cancel, 2016).

By situating HS at the intersection of genetics, endothelial mechanosensing, and shear-activated PEM, this framework reconciles disparate findings across immune, metabolic, and vascular studies without invoking excessive inflammation or mitochondrial failure as primary drivers. HS dysfunction thus provides a unifying, testable interface linking genetic predisposition to the characteristic delayed, load-dependent symptom exacerbation that defines ME/CFS (Florian et al., 2003; Weinbaum, Tarbell & Damiano, 2007; Huang et al., 2026; PrecisionLife Ltd., 2025; Tarbell & Cancel, 2016).

6.1 Why heparan sulfate is downstream — and why that matters

A central implication of the present analysis is that heparan sulfate (HS) dysfunction is best understood as downstream and conditional, rather than as a primary genetic lesion in ME/CFS. Across both genetic datasets examined, we found no evidence of direct enrichment for core HS biosynthetic or degradative genes, such as EXT family glycosyltransferases, NDST sulfotransferases, or heparanase (HPSE). This absence is notable, as it argues against a model in which ME/CFS is driven by constitutive defects in HS production or turnover (Huang et al., 2026; PrecisionLife Ltd., 2025).

Instead, the convergent genetic signal points to upstream control-layer fragility—including immune signal regulation, ER protein quality control, lipid and membrane stability, and extracellular matrix coupling—that conditions the environment in which HS must be synthesized, maintained, and repaired. In this context, HS occupies a vulnerable interface position: it is essential for endothelial shear sensing and signal precision, yet highly sensitive to inflammatory stress, oxidative injury, and impaired recovery mechanisms (Reitsma et al., 2007; Tarbell & Cancel, 2016; Florian et al., 2003; Weinbaum, Tarbell & Damiano, 2007).

This framing has important explanatory value. It accounts for why HS-targeted or endothelial-supportive interventions may produce heterogeneous and sometimes paradoxical clinical responses. If upstream control layers remain unstable, partial or transient improvement in HS-dependent mechanosensing may temporarily reduce symptoms without restoring true regulatory headroom. Increased activity during such windows could then amplify cumulative stress, leading to delayed worsening rather than sustained improvement. Conversely, in contexts where upstream stability is greater, similar interventions might be better tolerated. Recognizing HS as a downstream precision buffer rather than a primary driver thus helps reconcile mixed therapeutic observations without invoking contradictory mechanisms (Tarbell & Cancel, 2016).

6.2 Implications for PEM, Long COVID, and endothelial phenotypes

By situating HS at the intersection of genetic vulnerability and endothelial mechanosensing, this framework offers a unified interpretation of post-exertional malaise as a shear-activated failure state. In this model, PEM is not triggered by excessive exertion per se, but by the misprocessing of otherwise normal physiological shear when glycocalyx-dependent signal precision is compromised. This naturally explains the delayed and disproportionate nature of symptom exacerbation, as endothelial and microvascular signaling errors propagate over time rather than manifesting immediately (Tarbell & Cancel, 2016; Florian et al., 2003; Pahakis et al., 2007).

Beyond ME/CFS, this interpretation may have broader relevance for Long COVID and related post-infectious syndromes, where endothelial dysfunction, orthostatic intolerance, and exercise intolerance are common features. Symptoms such as postural lightheadedness, heat sensitivity, and cognitive load–induced crashes can all be conceptualized as contexts in which shear stress or flow redistribution increases demand on endothelial control surfaces. If HS-dependent mechanosensing is fragile, these everyday stressors may repeatedly expose control failure, producing fluctuating yet cumulative symptom burden (Wirth & Scheibenbogen, 2021; van Campen et al., 2020; Tarbell & Cancel, 2016).

Importantly, this framework does not imply that all patients share the same endothelial phenotype or degree of HS vulnerability. Rather, it suggests that shear sensitivity represents a common activation pathway, whose expression and severity are shaped by upstream genetic and environmental factors. This distinction preserves heterogeneity while offering a coherent physiological explanation for shared clinical patterns across post-viral conditions.

6.3 Limitations

Several limitations of the present analysis should be acknowledged. First, no direct genetic causation of HS dysfunction is demonstrated. The genetic associations discussed implicate upstream biological processes that condition HS integrity, but do not establish defects in HS biosynthesis, sulfation, or degradation as primary lesions in ME/CFS (Huang et al., 2026; PrecisionLife Ltd., 2025).

Second, the proposed model relies on functional inference and biological plausibility, integrating genetic enrichment with established endothelial and glycocalyx biology. While this approach is appropriate for hypothesis generation and framework building, it does not substitute for direct experimental validation (Florian et al., 2003; Weinbaum, Tarbell & Damiano, 2007; Tarbell & Cancel, 2016).

Finally, endothelial-level studies are needed to test key predictions of the model, including altered HS structure, impaired shear-induced NO signaling precision, and abnormal recovery dynamics following physiological stress in ME/CFS. Longitudinal and flow-sensitive measurements will be particularly important to distinguish primary capacity limitations from control and resolution failures (Pahakis et al., 2007; van Campen et al., 2020).

By explicitly acknowledging these constraints, the present work aims to provide a restrained yet integrative framework that can guide future mechanistic studies, rather than a definitive causal claim.