Preprint Genetic Insights into Circulating Complement Proteins in ME/CFS: A Potential Inflammatory Subgroup, 2025, Maya et al

[John Mac]

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 found associated with fatigue-related phenotypes in the UK biobank, 4 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 subgroup. This approach could identify pathway-focused subgroups in ME/CFS and similar illnesses to inform personalized approaches to diagnosis and treatments.

https://www.preprints.org/manuscript/202512.1773

 

[V.R.T.]

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 found associated with fatigue-related phenotypes in the UK biobank, 4 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 subgroup. This approach could identify pathway-focused subgroups in ME/CFS and similar illnesses to inform personalized approaches to diagnosis and treatments.

https://www.preprints.org/manuscript/202512.1773

This sounds interesting- is there anything to it?

 

[Dolphin]

This uses the Georgia cohort. This study had a prevalence of 2.54% compared to an earlier study using similar methodology of 0.235%. This huge difference was largely due to the use of the empiric criteria (Reeves et al 2005), a very odd way to define CFS. I have little confidence in the relevance of studies using this criteria.

4.1. Subject Recruitment and Characteristics This study included the 50 ME/CFS and 121 non-fatigued (NF) controls subjects from the previously published genetic analysis focusing on inflammatory and immune-related pathways [3]. Briefly, participants were identified in the follow-up phase of the longitudinal study of ME/CFS in Georgia. ME/CFS cases were identified with the operationalized 1994 international research case definition [84]. Sample characteristics such as age, sex, body mass index (BMI), illness duration and onset, and symptom and functioning scores across fatigue (multidimensional fatigue inventory, MFI 20), functional status (SF-36), CDC symptom inventory (CDC-SI), and routine clinical tests results (including hs-CRP) were recorded for every participant [3]. The source study was approved by the Institutional Review Board of the Centers for Disease Control and Prevention and Abt Associates (now Abt Global). All subjects gave written informed consent for participating in the study and for anonymous testing and storage of biologic samples.

84. Reeves, W.C., et al., Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Population Health Metrics, 2007. 5(1): p. 5.