ML-210 br Transparency document br Introduction Fatigue is
Introduction Fatigue is a condition of debilitating tiredness, lethargy and lack of ML-210 which manifests as a symptom of many different diseases and, more rarely, on its own (chronic fatigue syndrome, CFS, also known as myalgic encephalomyelitis, ME). The prevalence of fatigue may be as high as 50% in the general population, though in most cases it is transient and diminishes as the causal factor (e.g. viral infection) resolves , . Fatigue is a characteristic symptom of many chronic rheumatic conditions such as rheumatoid arthritis (RA), system lupus erythematous (SLE), and fibromyalgia. Patients with SLE and RA report persistent fatigue in up to 80–90% cases and there is no clear evidence that it is related to disease activity , , . Fatigue is also common in non-inflammatory conditions such as cancer and neurological disorders. Fatigue is often associated with chronic pain; in rheumatic diseases both the presence and the intensity of these symptoms are well correlated , , , . In patients with RA and SLE painful symptoms such as arthralgia are important contributing factors to fatigue severity; also, pain has been shown to be the strongest predictor of fatigue in many studies , , . Fatigue often occurs in fibromyalgia, a non-inflammatory condition manifesting chronic widespread pain (CWP) accompanied by sleep disturbance . Due to the strong co-morbidity of fibromyalgia and chronic fatigue some researchers debate they are a single syndrome caused by overlapping mechanisms . This is supported by a genetic epidemiology study that showed strong genetic correlation between CWP and fatigue, suggestive of the presence of shared genes and molecular pathways . On the other hand, other studies proposed that co-occurrence between fatigue and CWP is due to their share of common psychiatric component (anxiety and depression)  which also shares genetic determinants with CWP . The metabolome comprises the sum of small molecule chemicals (amino acids, lipids, fatty acids, sugars, vitamins, etc.) detectable in a sample, usually serum, plasma or urine. It represents the higher end of phenotypic expression of the genome and is, therefore, much closer to the phenotype of interest than, say, protein expression. Metabolomic studies are increasingly successful in identifying mechanisms of complex diseases and may reveal new targets for therapy and provide diagnostic and prognostic tools , , . We have recently demonstrated that individuals with CWP may present with an altered metabolic profile compared to healthy individuals . It is also supported by the findings that the risk of CWP increases with higher body mass index (BMI) . Furthermore, dietary risk factors which affect metabolite levels, including higher consumption of fats but lower consumption of fruit and vegetables, have been found in those with CWP . There are limited metabolome studies in fatigue , , , , , ,  and no studies have examined fatigue in the general population as opposed to a clinical sample. We investigated the circulating metabolome in a large sample of twins taken from the UK population. We were interested to determine whether there is a pattern of circulating metabolome specific for fatigue in people reporting CWP which might provide a diagnostic biomarker for this symptom.
Material and methods
Discussion This is the first population study of fatigue in CWP using metabolomics screening. We found fatigue associated with lower circulating levels of the eicosapentaenoate (EPA) ω-3 fatty acid in those with CWP. No association between EPA levels and CWP itself were seen either in the current study or in our earlier metabolome investigation of CWP alone . This suggests that the decrease of EPA is a characteristic metabolic feature of CWP-associated fatigue and may serve as a biomarker for this condition. It further suggests that CWP and fatigue do not fully overlap metabolically and do, therefore, represent distinct physiological syndromes. Our results are concordant with previous findings of EPA level decrease in patients with ME/CFS that suggested that ω-3 fatty acid availability is linked to immune pathophysiology of the syndrome .