Complement Component C1q as a Potential Diagnostic Tool for ME/CFS Subtyping, by Jesús Castro-Marrero, Mario Zacares, Eloy Almenar-Pérez,  José Alegre-Martín and Elisa Oltra in J. Clin. Med. 2021, 10(18), 4171; [] 15 September 2021


Research abstract:


Routine blood analytics are systematically used in the clinic to diagnose disease or confirm individuals’ healthy status. For myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), a disease relying exclusively on clinical symptoms for its diagnosis, blood analytics only serve to rule out underlying conditions leading to exerting fatigue. However, studies evaluating complete and large blood datasets by combinatorial approaches to evidence ME/CFS condition or detect/identify case subgroups are still scarce.


This study used unbiased hierarchical cluster analysis of a large cohort of 250 carefully phenotyped female ME/CFS cases toward exploring this possibility.


The results show three symptom-based clusters, classified as severe, moderate, and mild, presenting significant differences (p < 0.05) in five blood parameters. Unexpectedly the study also revealed high levels of circulating complement factor C1q in 107/250 (43%) of the participants, placing C1q as a key molecule to identify an ME/CFS subtype/subgroup with more apparent pain symptoms.


The results obtained have important implications for the research of ME/CFS etiology and, most likely, for the implementation of future diagnosis methods and treatments of ME/CFS in the clinic.

Excerpt from Conclusion:

In conclusion, this study identified a potential new player in the ME/CFS pathology, the C1q component of the complement system, affecting over 40% of cases. This finding paves the way for exploring a C1q-based standard lab assay to detect ME/CFS subtypes with relevant clinical and research implications. The understanding of the underlying pathomechanisms behind this finding is limited at present, granting further exploration of the observation.

Excerpt from Discussion:

Although clustering methods based on case symptoms have been useful in identifying autonomic phenotypes in CFS [25], they failed at detecting robust blood correlations between symptoms and individual blood parameters in our cohort (Figure 2). The approach did, however, show potential for differentiating cases with severe, moderate, or mild affection as defined by the five symptom scores used for clustering (Table 2 and Table 3).

The physiological significance of the findings, including the increased levels of C3 in severe and moderate with respect to mildly affected cases or the increased neutrophil count in severe ME/CFS by itself or in combination with LDL and cholesterol, as well as their involvement in symptom development or maintenance, remains to be elucidated.

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