{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:17:54Z","timestamp":1770815874797,"version":"3.50.1"},"reference-count":88,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms27031574","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T15:24:19Z","timestamp":1770305059000},"page":"1574","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Insights into Circulating Complement Proteins in Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: A Potential Inflammatory Subgroup"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3676-9076","authenticated-orcid":false,"given":"Jessica","family":"Maya","sequence":"first","affiliation":[{"name":"Division of High-Consequence Pathogens & Pathology, Centers for Disease Control & Prevention, Atlanta, GA 30329, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2925-5635","authenticated-orcid":false,"given":"Elizabeth R.","family":"Unger","sequence":"additional","affiliation":[{"name":"Division of High-Consequence Pathogens & Pathology, Centers for Disease Control & Prevention, Atlanta, GA 30329, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8286-6593","authenticated-orcid":false,"given":"Jin-Mann S.","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of High-Consequence Pathogens & Pathology, Centers for Disease Control & Prevention, Atlanta, GA 30329, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mangalathu S.","family":"Rajeevan","sequence":"additional","affiliation":[{"name":"Division of High-Consequence Pathogens & Pathology, Centers for Disease Control & Prevention, Atlanta, GA 30329, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"ref_1","unstructured":"Institute of Medicine (2015). 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