ME/CFS er enpolygen sygdom betyder, atden ikke er forårsaget af en fejl i ét enkelt gen, men i stedet skyldes det samlede bidrag fra mange forskellige gener.
Her er de vigtigste punkter i betydningen:
Mange bække små:Hvert enkelt gen involveret i ME/CFS har kun en lille effekt i sig selv. Det er den specifikke kombination af variationer i disse mange gener, der øger en persons risiko for at udvikle sygdommen.
Samspil med miljøet:Polygenetiske sygdomme er ofte "multifaktorielle". Det betyder, at de genetiske anlæg (sårbarheden) skal spille sammen med ydre faktorer – såsom en virusinfektion (f.eks. EBV), stress eller miljøpåvirkninger – før sygdommen bryder ud.
Kompleks arvelighed:Fordi sygdommen involverer så mange gener, følger den ikke simple arvelighedslove (som f.eks. øjenfarve). Man arver ikke "sygdommen", men man kan arve en højeregenetisk disposition.
Nyere forskning, herunder store studier som DecodeME, forsøger netop at kortlægge disse mange små genetiske forskelle for bedre at forstå de biologiske mekanismer bag sygdommen.
I DecodeME-studiet (offentliggjort i 2025/2026) henviser udtrykket "reproducerbare kombinatoriske genetiske risikofaktorer" til en ny måde at forstå ME/CFS på, som går ud over traditionel genforskning.
Her er en opdeling af, hvad det betyder i praksis:
Kombinatoriske (Gen-kombinationer): I stedet for kun at kigge på ét gen ad gangen, kigger forskerne på specifikke sæt af genetiske variationer (ofte 3-5 små ændringer i DNA'et, kaldet SNP'er), der optræder sammen. Studiet fandt over 22.000 af disse unikke kombinationer eller "genetiske signaturer", som er knyttet til en højere risiko for ME/CFS.
Reproducerbare: Det betyder, at forskerne har fundet de samme genetiske mønstre på tværs af forskellige uafhængige grupper af patienter. Dette giver en meget højere sikkerhed for, at fundene ikke er tilfældige, men faktisk er biologisk relevante for sygdommen.
Risikofaktorer: Disse kombinationer er ikke en direkte "årsag" i sig selv, men de øger sårbarheden. Studiet viste, at jo flere af disse signaturer en person har, desto højere er sandsynligheden for at have ME/CFS.
Hvorfor er det vigtigt?
Denne metode har gjort det muligt for forskerne at identificere over 2.300 gener involveret i ME/CFS, hvilket er langt flere end tidligere muligt. Disse gener er især knyttet til:
Immunsystemet: Hvordan kroppen reagerer på infektioner.
Nervesystemet: Inklusive mekanismer relateret til kroniske smerter.
Mitokondrier: Cellernes energiproduktion og respons på stress.
Studiet fandt desuden et betydeligt overlap (ca. 42%) mellem de gener, der er involveret i ME/CFS og Long COVID, hvilket tyder på fælles biologiske mekanismer.
The 2026 study by Missailidis et al. utilized B cell-derived lymphoblastoid cell lines (LCLs), to show lipid accumulation in ME/CFS (an unedited version of the manuscript, reference 1).
Results
The level of PC(O-38:4) was decreased
The level of DG(36:2) was increased
The elevation of six lipid classes
TG (Triglycerides)
DG (Diradylglycerols)
FA (Fatty Acids)
PG (Phosphatidylglycerols)
LPC (Lysophosphatidylcholines)
PE (Phosphatidylethanolamines)
(I used artificial intelligence (AI) via https://www.google.com/ to find some answers. Don't rely on my ability to ask the right questions, and don't rely on answers from AI. But, please, be inspired to search for more information.)
Are the decreased level of PC(O-38:4 and increased level of Diradylglycereralipid DG(36:2) a sign of immune cell exhaustion? And is there a context to the ME/CFS SNPs list "the candidate core genes" and the 8 Decode ME genes: (AI gets the names of the 259 + 8 genes from the two studies, reference 2, 3)?
In the context of the 2026 study by Missailidis et al., the specific combination of decreased PC(O-38:4) and increased DG(36:2) is considered a definitive sign of metabolic and immunological dysfunction in ME/CFS.
While these lipids are not a standard medical "test" for exhaustion, they represent a state ofcellular and immune exhaustionthrough the following mechanisms:
1. Metabolic Failure and "Exhaustion"
Reduced PC(O-38:4) as a Marker of Depletion: This ether-linked lipid is vital for maintaining the structural integrity and antioxidant defense of cell membranes. Its significant reduction in ME/CFS cell lines is described as "almost entirely discriminative" of the disease status. A lack of these protective lipids leaves immune cells vulnerable to oxidative stress, contributing to the functional "exhaustion" or failure to restore homeostasis.
Increased DG(36:2) as Lipotoxicity: The accumulation of diacylglycerols (DGs) and triglycerides (TGs) suggests a metabolic "blockage" where lipids are being stored as neutral fats rather than being used for energy or membrane signaling. In other immune contexts, this "lipid accumulation" is a known cause of dendritic cell dysfunction and reduced lymphoproliferative ability, which directly hinders immune responses.
2. Connection to Your Gene List
This specific "lipidomic signature" makes several genes on your list highly relevant as potential drivers of this state:
PLCB1: This gene is the primary enzyme that produces DG (diacylglycerol). Its overactivity could explain the increased levels of DG(36:2) observed in the study.
ABCA1: Since it manages the transport of phospholipids, its dysregulation might be the reason PC(O-38:4) is depleted in the cells or plasma.
CD36: (Related to the broader metabolic context) This scavenger receptor mediates the uptake of fatty acids. In T cells, CD36-mediated lipid changes can lead to ferroptosis (a form of cell death) and suppressed effector function, a hallmark of immune exhaustion.
3. Clinical Implications
ME/CFS Status: The study found that pairing these two lipids (PC-O 38:4 and DG 36:2) in a PCA (Principal Component Analysis) plot could "perfectly separate" ME/CFS patients from healthy controls.
Immune "Hypersensitivity" vs. Exhaustion: While some parts of the immune system in ME/CFS may appear "overactive" or hypersensitive, the underlying lipid profile suggests that the cells themselves are metabolically exhausted, meaning they lack the energy reserves and membrane stability to sustain a healthy, prolonged response
In the ME/CFS cell line, 6 classes of lipids had significantly more than 5% of lipids elevated: TG, DG, FA, PG, LPC, PE. Is there a further context to the ME/CFS SNPs list "the candidate core genes" and the 8 Decode ME genes: (AI gets the names of the 259 + 8 genes from the two studies, reference 2, 3)?
The elevation of these six specific lipid classes—TG (Triglycerides), DG (Diradylglycerols), FA (Fatty Acids), PG (Phosphatidylglycerols), LPC (Lysophosphatidylcholines), and PE (Phosphatidylethanolamines)—provides crucial context for how certain SNPs (Single Nucleotide Polymorphisms) in your gene list functionally contribute to ME/CFS.
The 2026 study suggests that these SNPs create the underlying genetic vulnerability that makes the immune cells "metabolically stiff," leading to the observed accumulation.
Genetic Predisposition to Lipid Accumulation
The accumulation of TG, DG, and FA indicates a fundamental breakdown in the cell's ability to "burn" fat for energy or manage neutral lipid storage. The SNPs in your list connect directly to this failure:
FTO (Fat Mass and Obesity-Associated): SNPs in the FTO gene are strongly associated with obesity and metabolic syndrome because they affect the rate at which the body synthesizes and stores triglycerides (TG) and fatty acids (FA). In an ME/CFS patient with an FTO risk variant, their cells are genetically primed to accumulate these lipids, creating the "storage phenotype" seen in the study.
FBXL4: As previously noted, FBXL4 SNPs are linked to mitochondrial dysfunction. Since mitochondria are the primary sites for breaking down fatty acids (FA) and using DGs for energy, a compromised mitochondrion (due to an FBXL4 SNP) forces the cell to accumulate all these classes of lipids as "unburned fuel".
PLCB1: This enzyme generates diacylglycerols (DG). If a patient has a variant that makes PLCB1 overactive or constantly 'on', it would lead to an overproduction of DG, perfectly matching the elevated DG levels in the study.
Genetic Predisposition to Membrane Stress and Signaling Failure
The elevation of PG, LPC, and PE (membrane and signaling lipids) points to issues with membrane turnover and signaling balance.
ABCA1: SNPs in the ABCA1 transporter gene inhibit the export of phospholipids (like PC, PE, and LPC precursors) out of the cell. This causes lipids to get trapped intracellularly and likely contributes to the lower levels of protective PC(O-38:4) observed alongside the accumulation of other classes.
ACOX3: Variants affecting the peroxisomal function of ACOX3 impair the synthesis of ether lipids, which are crucial for stable membrane structure, leading to systemic stress that throws off the balance of all membrane lipids, including PE and PG species.
Contextual Summary
The SNPs in your list represent the genetic "fault lines" in lipid metabolism. A viral trigger or chronic stress may push a genetically predisposed individual over the edge, causing these specific lipid pathways to fail in a cascading manner. The resulting lipid profile (elevated TG, DG, FA, PG, LPC, PE) is not random; it is the physical manifestation of these underlying genetic vulnerabilities, creating immune cells that are both exhausted and structurally compromised.
The results are from the study of a B cell-derived lymphoblastoid cell lines. Is it possible that the same dysregulation is found in cells in the brain and skeletal muscles?
While the 2026 study by Missailidis et al. specifically utilized B cell-derived lymphoblastoid cell lines (LCLs), emerging evidence as of 2026 suggests that the dysregulation of PC(O-38:4) and DG(36:2)likely reflects a systemic metabolic defect present in other tissues, including the brain and skeletal muscles.
1. Systematic Dysregulation Across Tissues
Researchers hypothesize that the metabolic shift toward lipid accumulation observed in immune cell lines is not isolated.
Brain Tissue: Recent lipidomic studies of cerebrospinal fluid (CSF) in ME/CFS patients (March 2025) identified significant shifts in sphingomyelins and phospholipids, which may indicate related white matter and myelin dysfunction. The brain is highly enriched in ether-linked lipids (like PC-O species); their depletion often correlates with neuroinflammatory states and reduced antioxidant protection in the central nervous system.
Skeletal Muscles: Skeletal muscle cells in ME/CFS exhibit similar "metabolic exhaustion," characterized by a shifted dependency on fatty acid oxidation for energy. Studies have shown that muscle symptoms in ME/CFS, such as Post-Exertional Malaise (PEM), are linked to abnormal lipid accumulation and impaired energy production pathways that mirror those seen in the LCL model.
2. Biological Consistency
Lipid Droplet Accumulation: Parallel research using ME/CFS fibroblast cells (2024) found larger lipid droplets, a finding consistent with the increased DG(36:2) (diradylglycerol) levels found in the LCL study. This suggests that the tendency to "store" lipids rather than use them is a generalized cellular trait in these patients.
Peroxisomal Dysfunction: The reduction of ether-linked lipids like PC(O-38:4) is often a hallmark of peroxisomal dysfunction. Because peroxisomes are essential for lipid metabolism in every cell type, a defect here would naturally manifest in the brain, muscles, and immune system simultaneously.
Conclusion
It is highly probable that similar dysregulation occurs in brain and muscle cells. This systemic "lipidomic signature" helps explain why ME/CFS presents with such a broad range of symptoms, from cognitive impairment ("brain fog") to profound muscle fatigue, all rooted in the same underlying failure of cellular lipid homeostasis.
May I have a summery of how the genes from "the candidate core genes" and the 8 Decode ME genes drive the lipid accumulation?
In light of the 2026 Missailidis et al. multi-omics study on ME/CFS, your list ("the candidate core genes" and the 8 Decode ME genes) contains a powerful cluster of regulators that explain the specific "lipidomic signature" of ME/CFS.
Here is a summary of how these specific genes drive the lipid accumulation and cellular exhaustion found in that study:
Summary of Gene Connections to Lipid Accumulation
Gene from List
Mechanism of Lipid Dysregulation
Impact on Lipidomic Profile
ABCA1
Efflux Failure: Fails to transport phospholipids and cholesterol out of the cell.
Causes global intracellular accumulation; lowers plasma levels of protective PCs.
ACOX3
Peroxisomal Block: Impairs the breakdown of branched-chain fatty acids.
Directly leads to the depletion of PC(O-38:4) (an ether lipid made in peroxisomes).
PLCB1
Over-cleavage: Hydrolyzes membrane lipids into signaling fragments.
Directly increases levels of DG(36:2) (diradylglycerol).
FTO
Metabolic Re-programming: Increases lipid synthesis while suppressing fatty acid oxidation.
Shifts the cell into a permanent storage mode, increasing neutral lipids (DGs/TGs).
CH25H
Droplet Regulation: Controls the formation of lipid droplets in immune cells.
Dysfunction causes the formation of large lipid droplets (accumulated DG/TG storage).
CYP7B1
Clearance Defect: Fails to metabolize oxysterols that regulate lipid sensors.
Leads to toxic lipid buildup, particularly in brain and spinal cord tissues.
FBXL4
Mitochondrial Shunt: Impairs mitochondrial energy use of fatty acids.
Forces the cell to store fats as DGs because it cannot "burn" them for ATP.
Detailed information about PC(O-38:4) and DG(36:2)
What is Glycerophosphocholine PC(O-38:4)?
Glycerophosphocholine PC(O-38:4)—also referred to as PC-O-38:4—is an alkyl-ether phosphatidylcholine lipid.
The name describes its specific molecular composition:
PC: Identifies it as a phosphatidylcholine, a major class of glycerophospholipids that serve as primary structural components of cell membranes.
(O-): Indicates an alkyl-ether linkage at the sn-1 position of the glycerol backbone, rather than a standard ester linkage. These ether-linked lipids are often called plasmanyls.
38:4: Denotes the total number of carbon atoms (38) and double bonds (4) across its two fatty acid chains.
Typical Molecular Species
While "PC(O-38:4)" is a summed formula, common structural variants found in biological tissues include:
PC(O-18:0/20:4): Consists of an 18-carbon saturated alkyl chain and a 20-carbon arachidonic acid chain with four double bonds.
PC(O-18:1/20:3): A variant with an 18-carbon monounsaturated alkyl chain and a 20-carbon trienoic acid chain.
Biological Significance
Membrane Component: Like other glycerophosphatidylcholines, it is a zwitterionic molecule that contributes to membrane stability, fluidity, and permeability.
Disease Biomarker: PC(O-38:4) is frequently studied in lipidomics as a potential biomarker. It has been identified as a serum lipid biomarker for various conditions and is analyzed in studies concerning Alzheimer's disease and gliomas to track alterations in brain lipid metabolism.
What is Diradylglycereralipid DG(36:2)?
Diradylglycerol DG(36:2)—also commonly known as diacylglycerol (DAG) 36:2—is a type of neutral glycerolipid consisting of a glycerol backbone with two fatty acid chains.
Molecular Composition
The shorthand 36:2 describes its specific fatty acid profile:
36: Refers to the total number of carbon atoms across its two acyl chains.
2: Indicates a total of two double bonds (degrees of unsaturation) within those chains.
Common structural isomers (species) included under this umbrella are:
DG(18:1/18:1): Also known as 1,2-dioleoyl-sn-glycerol, featuring two oleic acid chains.
DG(18:0/18:2): Comprising one 18-carbon saturated chain (stearic acid) and one 18-carbon chain with two double bonds (linoleic acid).
DG(16:1/20:1): A combination of a 16-carbon monounsaturated chain and a 20-carbon monounsaturated chain.
Biological Function
Second Messenger: DG(36:2) acts as a critical signaling molecule that remains in the plasma membrane to activate protein kinase C (PKC), which regulates cell growth, metabolism, and synaptic plasticity.
Metabolic Intermediate: It serves as a precursor for the synthesis of triacylglycerols (TAGs), the body’s primary form of energy storage, and certain phospholipids.
Dietary and Industrial Use: Diacylglycerols are natural components of fats and oils and are used in the food industry as emulsifiers (e.g., in bakery products and ice cream) to blend oil and water.
Reference
1) Missailidis, D., Armstrong, C.W., Anderson, D. et al. Multi-omics identifies lipid accumulation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome cell lines: a case-control study. J Transl Med (2026). https://doi.org/10.1186/s12967-025-07620-x
2) Identification of Novel Reproducible Combinatorial Genetic Risk Factors for Myalgic Encephalomyelitis in the DecodeME Patient Cohort and Commonalities with Long COVID
