Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an unexplained chronic, debilitating illness characterized by fatigue, sleep disturbances, cognitive dysfunction, orthostatic intolerance and gastrointestinal problems. Using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we analyzed the plasma proteomes of 39 ME/CFS patients and 41 healthy controls. Logistic regression models, with both linear and quadratic terms of the protein levels as independent variables, revealed a significant association between ME/CFS and the immunoglobulin heavy variable (IGHV) region 3-23/30. Stratifying the ME/CFS group based on self-reported irritable bowel syndrome (sr-IBS) status revealed a significant quadratic effect of immunoglobulin lambda constant region 7 on its association with ME/CFS with sr-IBS whilst IGHV3-23/30 and immunoglobulin kappa variable region 3–11 were significantly associated with ME/CFS without sr-IBS. In addition, we were able to predict ME/CFS status with a high degree of accuracy (AUC = 0.774–0.838) using a panel of proteins selected by 3 different machine learning algorithms: Lasso, Random Forests, and XGBoost. These algorithms also identified proteomic profiles that predicted the status of ME/CFS patients with sr-IBS (AUC = 0.806–0.846) and ME/CFS without sr-IBS (AUC = 0.754–0.780). Our findings are consistent with a significant association of ME/CFS with immune dysregulation and highlight the potential use of the plasma proteome as a source of biomarkers for disease.
Highlights
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown cause that affects up to 2.5 million people in the USA alone [1]
Using a model that included both linear and quadratic terms we found a significant association between ME/CFS and IGHV3-23/30
Its usage has been linked with non-Hodgkin lymphomas (NHL) such as chronic lymphoid leukemia (CLL) [31,32,33,34], mantle cell lymphoma (MCL) [35], splenic marginal zone lymphoma (MZL) [36, 37], Waldenstrom’s macroglobulinemia [38], and follicular lymphoma (FL) [39, 40]
Summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown cause that affects up to 2.5 million people in the USA alone [1]. The disease is defined by persistent fatigue lasting longer than six months, post-exertional malaise, unrefreshing sleep, and either cognitive dysfunction or orthostatic intolerance [1]. These symptoms are often accompanied by others that may include chronic pain, influenza-like symptoms, and gastro-intestinal disturbances [2]. Another study of cerebrospinal fluid by Schutzer et al (2011) [12] showed differing proteomic profiles between ME/CFS and post-treatment Lyme disease patients that included enrichment in the ME/CFS group of proteins involved in the complement cascade as well as pathways related to CDK5 signaling and dopamine signaling. Another study of the platelet mitochondrial proteome in the same pair of twins identified upregulation of aconitate hydratase, ATP synthase subunit beta, and malate dehydrogenase that was replicated in saliva of a larger cohort of 45 subjects with ME/CFS [14]
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