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

Area of Science:

• Immunogenetics
• Systems Biology
• Complex Diseases

Background:

• Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system illness with poorly understood pathophysiology.
• Immune dysregulation, particularly involving the complement system, is implicated in ME/CFS pathogenesis.
• The heterogeneity of ME/CFS complicates the identification of biomarkers and therapeutic targets.

Purpose of the Study:

• To investigate the role of genetic factors in complement pathway dysregulation in ME/CFS.
• To identify specific genetic variants associated with complement protein levels in ME/CFS patients.
• To explore the link between genetic drivers, complement dysregulation, and inflammatory subgroups within ME/CFS.

Main Methods:

• Utilized protein quantitative trait loci (pQTL) analyses in a cohort of ME/CFS patients and non-fatigued controls.
• Employed linear and logistic regression models, adjusting for relevant covariates.
• Validated findings using data from the UK Biobank to assess associations with fatigue-related phenotypes.

Main Results:

• Identified significant pQTLs associated with plasma complement protein levels in ME/CFS patients.
• Discovered that specific pQTLs are linked to alternative complement pathway dysregulation, defining an inflammatory subgroup (high C3/low Bb).
• Found associations between six significant pQTLs and fatigue phenotypes in the UK Biobank, with four being complement-associated.

Conclusions:

• Established a genetic basis for complement dysregulation in a subset of ME/CFS patients, contributing to disease heterogeneity.
• Highlighted a mechanism involving risk alleles influencing complement pathway function in ME/CFS.
• Demonstrated the potential of this genetic approach to identify pathway-focused subgroups for personalized medicine in ME/CFS and related disorders.