Evaluating the Causal Role of Genetically Inferred Immune Cells and Inflammatory Cytokines on ME/CFS, 2025, Duan et al

https://www.mdpi.com/2227-9059/13/5/1200

Abstract
Background/Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted and diverse disorder with an ambiguous etiology. Recent evidence indicates that immune system impairment and inflammatory mechanisms are pivotal to the initiation and advancement of ME/CFS. Nonetheless, the causal relationships among these factors remain inadequately comprehended.

Methods: This study investigated the causative contributions of immunological dysfunction and inflammatory variables in ME/CFS utilizing genome-wide association study (GWAS) data. We employed Mendelian randomization (MR) to investigate associations between 91 inflammatory cytokines, 731 immune cell characteristics, and the risk of ME/CFS. Summary statistics for immune cell traits and inflammatory cytokines were sourced from European GWAS cohorts (n = 3757 and n = 14,824, respectively), while ME/CFS data were obtained from the UK Biobank (n = 462,933, including 2076 cases). We predominantly employed the inverse variance weighted (IVW) approach, complemented by MR-Egger, weighted median, BWMR, and MR-RAPS tests to guarantee robust and precise outcomes.

Results: The study revealed significant causal links between various inflammatory factors, immune cell characteristics, and the risk of ME/CFS. Increased CXCL5 and CCL20 levels were significantly linked to a higher risk of ME/CFS, while elevated TNF levels were inversely related to ME/CFS risk. Furthermore, 13 immune cell characteristics were identified as having substantial causal associations with the likelihood of ME/CFS. These data are supportive of the causality that immune system dysfunction and inflammatory variables play a pivotal role in the development of ME/CFS.

Conclusions: This study provides new insights into the causal role of immune system dysfunction in the development of ME/CFS, contributing to a deeper understanding of its underlying mechanisms. These results offer a foundation for identifying diagnostic biomarkers and developing targeted therapeutic strategies. Future research should validate these findings using multi-center cohort studies and further investigate the mechanisms behind key factors to enable the development of personalized treatment approaches.

 

Is «causal links» appropriate here?

 

Probably not.
For a couple reasons but the one that stands out to me is “Horizontal Pleiotropy”. Ie. a single SNP may influence many different things and we might only know about some. So assuming the cytokines play a causal role in ME/CFS according to some SNP variations linked to cytokines and ME/CFS is probably not fully supported. Since those SNPs might be doing something else as well and that could be what links it to ME/CFS.

 

The structure of a mendelian randomization study enables you to claim causation, but only if certain criteria are adequately met. There was some discussion of MR studies in this thread: https://www.s4me.info/threads/evidence-for-a-causal-association-between-human-cmv-infection-and-chronic-back-pain-a-one‐sample-mendelian-randomization-study-2025-naeini-et-al.43598/

I'm no expert in MR, but from my brief skimming, this paper does seem to do a good job of addressing those criteria [edit: though it does have the limitation of being a two sample rather than one-sample study]. If there does happen to be a genetics expert on the forum I'd definitely appreciate hearing their assessment.