Haptoglobin phenotypes and structural variants associate with post-exertional malaise and cognitive dysfunction in myalgic encephalomyelitis. — CFSMEATLAS
Haptoglobin phenotypes and structural variants associate with post-exertional malaise and cognitive dysfunction in myalgic encephalomyelitis.
Moezzi, Atefeh, Ushenkina, Anastasiya, Widgren, Anna et al. · Journal of translational medicine · 2025 · DOI
Quick Summary
Researchers studied a protein called haptoglobin in people with ME/CFS and found it may be connected to post-exertional malaise (that worsening of symptoms after activity) and brain fog. They discovered that certain genetic variations of this protein were more common in ME/CFS patients, and those variations were linked to worse symptoms and cognitive problems. The study suggests haptoglobin could be a useful marker to help doctors understand why ME/CFS symptoms vary between patients.
Why It Matters
Identifying a potential biological marker like haptoglobin could help ME/CFS patients in multiple ways: doctors might use it to predict who will have worse post-exertional symptoms, identify subgroups for targeted treatments, and develop new therapies aimed at reducing oxidative stress. This moves ME/CFS research closer to precision medicine approaches that account for the disease's clinical heterogeneity.
Observed Findings
ME/CFS patients showed significant reduction in haptoglobin levels following post-exertional stress compared to controls.
Lower baseline haptoglobin concentrations were associated with worse cognitive performance in ME/CFS patients.
Haptoglobin Hp2-1 phenotype was enriched in ME/CFS patients and linked to greater post-exertional malaise severity.
Hp2-1 subgroup demonstrated altered proteoform profiles with increased high-mass tetrameric and pentameric forms on HPLC analysis.
Haptoglobin Hp1-1 phenotype associated with milder symptoms and greater cognitive resilience compared to other phenotypes.
Inferred Conclusions
Haptoglobin phenotype and structural proteoform composition modulate physiological response to post-exertion in ME/CFS and contribute to clinical heterogeneity of the disease.
Haptoglobin may serve as a translational biomarker for patient stratification and risk stratification of PEM and cognitive dysfunction severity.
Targeting haptoglobin or its associated oxidative stress pathways could represent a potential therapeutic strategy for mitigating PEM and cognitive symptoms.
Remaining Questions
Does haptoglobin phenotype predict individual responses to specific ME/CFS treatments, and could it guide personalized therapy selection?
What This Study Does Not Prove
This study does not prove that haptoglobin phenotype causes post-exertional malaise or cognitive dysfunction—only that they are associated. The findings cannot yet explain whether changing haptoglobin levels would improve symptoms, and results from this single cohort require replication in larger, diverse populations before clinical use. The study does not establish which came first: the altered haptoglobin patterns or the ME/CFS symptoms.
What are the upstream mechanisms causing altered haptoglobin levels and proteoforms in ME/CFS—are they primary or secondary to other disease processes?
Can haptoglobin-targeted interventions (such as antioxidant therapies) actually improve post-exertional malaise and cognitive symptoms in ME/CFS patients?
How stable are haptoglobin phenotypes and proteoform profiles over time within individual ME/CFS patients, and do they change with disease progression?