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

## TL;DR

This study explores how genetic variations may contribute to immune system dysregulation in a subset of ME/CFS patients, potentially identifying an inflammatory subgroup.

## Contribution

The study identifies genetic variants linked to complement protein dysregulation in ME/CFS, defining an inflammatory subgroup with a specific C3/low Bb profile.

## Key findings

- ME/CFS patients with certain pQTLs showed dysregulation of the alternative complement pathway.
- Six pQTLs were associated with fatigue-related phenotypes in the UK Biobank, four of which were complement-related.
- The findings suggest a genetic basis for complement dysregulation in a subset of ME/CFS patients.

## Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-system illness with heterogeneity that complicates identifying the pathophysiology, biomarkers, and therapeutic targets. Evidence indicates the importance of immune dysregulation, including the complement system, in ME/CFS. This study investigates the contribution of genetic drivers to potential dysregulation of the complement pathway in ME/CFS. We used protein quantitative trait loci (pQTL) analyses, adjusted for covariates using linear and logistic regression, to identify genetic variants significantly associated with plasma complement protein levels in a study sample identified from the general population (50 ME/CFS and 121 non-fatigued). ME/CFS patients carrying certain pQTLs exhibited dysregulation of the alternative complement pathway, which defined an inflammatory subgroup with a high C3/low Bb profile and established a genetic link to dysregulation of the alternative complement pathway. Six of the significant pQTLs were also associated with fatigue-related phenotypes in the UK Biobank, four of which were complement-associated, providing some validation in an independent population. Our findings highlight a mechanism by which risk alleles contribute to ME/CFS heterogeneity, providing evidence of a genetic basis for complement dysregulation in a subset of patients. This approach could identify pathway-focused subgroups in ME/CFS and related illnesses to inform personalized approaches to diagnosis and treatment.