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Polymorphisms in genes regulating HPA axis associated with empirically delineated classes of unexplained chronic fatigue

Centers for Disease Control and Prevention, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, 1600 Clifton Road, MSG41, Atlanta, GA 30333, USA.
Pharmacogenomics (Impact Factor: 3.43). 05/2006; 7(3):387-94. DOI: 10.2217/14622416.7.3.387
Source: PubMed

ABSTRACT Chronic fatigue syndrome (CFS) is characterized by persistent or relapsing fatigue that is not alleviated by rest, causes substantial reduction in activities and is accompanied by a variety of symptoms. Its unknown etiology may reflect that CFS is heterogeneous. Latent class analyses of symptoms and physiological systems were used to delineate subgroups within a population-based sample of fatigued and nonfatigued subjects [1] . This study examined whether genetic differences underlie the individual subgroups of the latent class solution. Polymorphisms in 11 candidate genes related to both hypothalamic-pituitary-adrenal (HPA) axis function and mood-related neurotransmitter systems were evaluated by comparing each of the five ill classes (Class 1, n = 33; Class 3, n = 22; Class 4, n = 22; Class 5, n = 17; Class 6, n = 11) of fatigued subjects with subjects defined as well (Class 2, n = 35). Of the five classes of subjects with unexplained fatigue, three classes were distinguished by gene polymorphsims involved in either HPA axis function or neurotransmitter systems, including proopiomelanocortin (POMC), nuclear receptor subfamily 3, group C, member 1 (NR3C1), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and tryptophan hydroxylase 2 (TPH2). These data support the hypothesis that medically unexplained chronic fatigue is heterogeneous and presents preliminary evidence of the genetic mechanisms underlying some of the putative conditions.

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    • "Notably, NR3C1 and 27 other genes (out of several million possible polymorphisms ) were highly predictive of people developing CFS (Goertzel et al., 2006). Concordant with these findings , Smith et al. (2006) reported that three out of five clinically distinct classes of fatigued people were associated with multiple genes known to be involved in HPA axis and neurotransmitter regulation. Furthermore , one study identified positive associations of cytokine-related polymorphisms in CFS (Carlo-Stella et al., 2006), suggesting a role for the immune system in the manifestation of CFS. "
    Handbook of Clinical Neurology 01/2012; 106:573-87. DOI:10.1016/B978-0-444-52002-9.00034-6
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    • "Notably, NR3C1 and 27 other genes (out of several million possible polymorphisms ) were highly predictive of people developing CFS (Goertzel et al., 2006). Concordant with these findings , Smith et al. (2006) reported that three out of five clinically distinct classes of fatigued people were associated with multiple genes known to be involved in HPA axis and neurotransmitter regulation. Furthermore , one study identified positive associations of cytokine-related polymorphisms in CFS (Carlo-Stella et al., 2006), suggesting a role for the immune system in the manifestation of CFS. "
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    ABSTRACT: DEFINITION Chronic fatigue syndrome (CFS) is a complex illness de-fined by unexplained disabling fatigue as its core feature and a combination of other accompanying symptoms, such as diffuse pain, subjective cognitive impairment, and sleep problems. Similar symptom constellations have been described for at least two centuries and a changing list of names has been used to label them: neurasthenia, neuromyasthenia, myalgic encephalomyelitis, myalgic en-cephalopathy, poliomyelitis-like illness, Akureyri disease, postviral fatigue, and chronic mononucleosis are some examples (Straus, 1991; Briggs and Levine, 1994). The first formal case definition of the illness, published in the USA in 1988 (Holmes et al., 1988), suggested the name "chronic fatigue syndrome" or CFS. In 1994, an interna-tional collaborative group that included authors of the previous case definitions published the current CFS re-search case definition (Fukuda et al., 1994). The 1994 case definition requires at least 6 months of persistent fatigue; this fatigue cannot be substantially alleviated by rest, is not the result of ongoing exertion, and is associated with substantial reductions in occupational, social, and per-sonal activities. In addition, at least four of the following eight symptoms must occur with fatigue in a 6-month period: (1) impaired memory or concentration; (2) sore throat; (3) tender glands; (4) aching or stiff muscles; (5) multijoint pain; (6) new headaches; (7) unrefreshing sleep; and (8) postexertional fatigue. Medical conditions that may explain the prolonged fatigue as well as a number of psychiatric diagnoses exclude a patient from the diag-nosis of CFS (Reeves et al., 2003). More recently, efforts have been made to assess case-defining symptoms of CFS objectively. Persons are classified as having CFS if they meet the following three empirically derived criteria as assessed by psychometrically evaluated questionnaires (Reeves et al., 2005): (1) severe fatigue; (2) substantial functional impairment; and (3) presence of substantial accompanying symptoms. Because CFS is a diagnosis of exclusion, a thorough medical history and assessment are required before the diagnosis can be formally established. As outlined in a recommendation of the International CFS Study Group (Reeves et al., 2003), the following medical conditions should be considered as permanent exlcusions: (1) organ failure (e.g., emphysema, cirrhosis, cardiac failure, chronic renal failure); (2) chronic infections (e.g., ac-quired immunodeficiency syndrome (AIDS), hepatitis B or C); (3) rheumatic and chronic inflammatory dis-eases (e.g., systemic lupus erythematosus, Sj€ ogren's syndrome, rheumatoid arthritis, inflammatory bowel disease, chronic pancreatitis); (4) major neurologic dis-eases (e.g., multiple sclerosis, neuromuscular diseases, epilepsy or other diseases requiring ongoing medication that could cause fatigue, stroke, head injury with resid-ual neurologic deficits); (5) diseases requiring systemic treatment (e.g., organ or bone marrow transplantation, systemic chemotherapy, radiation of brain, thorax, ab-domen, or pelvis); (6) major endocrine diseases (e.g., hy-popituitarism, adrenal insufficiency); and (7) primary sleep disorders (e.g., sleep apnea, narcolepsy). Temporary medical exclusions include treatable con-ditions that require evaluation over time to determine the extent to which they contribute to the fatigu-ing illness. These encompass four general categories: (1) conditions discovered at onset or initial evaluation (e.g., effects of medications, sleep deprivation, untreated hypothyroidism, untreated or unstable diabetes mellitus, active infection); (2) conditions that resolve (e.g., preg-nancy until 3 months postpartum, breastfeeding, major surgery until 6 months postoperation, minor surgery until *Correspondence to:
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    • "A genetic study by Rajeevan et al. (2006) also implicated cortisol regulatory mechanisms in ME/CFS, finding that single nucleotide polymorphisms in the glucocorticoid receptor (GR) gene were associated with increased risk for ME/CFS [33]. Previous work has found variance in the expression of GR (NR3C1) in individuals with ME/CFS when compared to controls [34]. Those with ME/CFS may have decreased sensitivity to the effects of cortisol due to a down-regulation of GR [20]. "
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    ABSTRACT: Kindling might represent a heuristic model for understanding the etiology of Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Kindling occurs when an organism is exposed repeatedly to an initially sub-threshold stimulus resulting in hypersensitivity and spontaneous seizure-like activity. Among patients with ME/CFS, chronically repeated low-intensity stimulation due to an infectious illness might cause kindling of the limbic-hypothalamic-pituitary axis. Kindling might also occur by high-intensity stimulation (e.g., brain trauma) of the limbic-hypothalamic-pituitary axis. Once this system is charged or kindled, it can sustain a high level of arousal with little or no external stimulus and eventually this could lead to hypocortisolism. Seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur among patients with ME/CFS. In addition, kindling may also be responsible for high levels of oxidative stress, which has been found in patients with ME/CFS.
    03/2011; 2(1):14-27. DOI:10.4236/nm.2011.21003
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