Genetic Insights into Circulating Complement Proteins in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Potential Inflammatory Subgroup.

Observed Findings

• ME/CFS patients carrying certain pQTL variants exhibited dysregulation of the alternative complement pathway with a characteristic high C3/low Bb protein profile.
• Six significant pQTLs identified in the ME/CFS cohort showed association with fatigue-related phenotypes in the independent UK Biobank population.
• Four of the UK Biobank-validated pQTLs were complement-associated, providing cross-population confirmation.
• The study identified an inflammatory subgroup within the ME/CFS population defined by specific genetic and complement protein signatures.
• Genetic variants linked to complement dysregulation were specifically present in ME/CFS patients rather than uniformly distributed across controls.

Inferred Conclusions

• Genetic variation contributes to heterogeneity in ME/CFS by predisposing certain patients to complement pathway dysregulation.
• Complement dysregulation represents a biologically-driven subphenotype of ME/CFS with genetic basis, rather than a universal disease mechanism.
• Pathway-specific genetic profiling could enable identification of patient subgroups amenable to targeted immunological treatments.
• Personalized medicine approaches in ME/CFS should incorporate genetic and biomarker-defined subgroup classification.

Remaining Questions