Autoimmune Thyroid Disease

An Unfortunate and Lengthy Adventure in Misdiagnosis

The genetics of chronic fatigue syndrome

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To begin with, here is an overview of the frequency of CFS and the factors thought to be involved:

The US case definition of CFS (the CDC-definition) is most widespread in research and clinical practice. Estimates of prevalence vary from 0.2% to above 2%. The female-male ratio is approximately 3:1. […] Present knowledge suggests that certain genetic polymorphisms and personality traits might be regarded as predisposing factors, some infections and severe psychosocial stress constitute precipitating factors, whereas disturbances of immunity, skeletal muscle, cognitive abilities, endocrine control and cardiovascular homeostasis are possible perpetuating factors. The chronic fatigue syndrome–an update

Angiotension converting enzyme (ACE) deletions are associated with Gulf War Syndrome:

Increased risk for CFS/ICF was associated with alterations of the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene within the Gulf War veteran sample only. […] Veterans with the DD genotype were eight times more likely to develop CFS/ICF than were those with the II genotype. Association of medically unexplained fatigue with ACE insertion/deletion polymorphism in Gulf War veterans

Corticosteroid-binding globulin (CBG) polymorphisms are associated with CFS:

A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized that CBG gene polymorphisms may act as a genetic risk factor for CFS. […] Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G–>T, Ala-Ser224). Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies. A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted, compared with controls […] Despite higher CBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients […] Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions. Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism

Serotonin (5-hydroxy-tryptamine) transport protein (5-HTT, also known as SERT) polymorphisms are associated with CFS:

Interaction between the hypothalamo-pituitary-adrenal axis and the serotonergic system is thought to be disrupted in chronic fatigue syndrome (CFS) patients. We examined a serotonin transporter (5-HTT) gene promoter polymorphism, which affects the transcriptional efficiency of 5-HTT […] A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls […] Attenuated concentration of extracellular serotonin due to longer variants may cause higher susceptibility to CFS. Association between serotonin transporter gene polymorphism and chronic fatigue syndrome

We have recently reported the association of serotonin transporter gene polymorphism in CFS. A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls. Compared to S allele, the L allele is believed to retain higher transcriptional activity, which causes decreased concentration of serotonin in the extracellular space, namely, active serotonin in CFS. These results thus support the serotonin hypothesis in the pathogenesis of CFS. Genetic background of chronic fatigue syndrome

Having serotonin levels that are too low can be caused by genetics, or by a viral infection:

Attenuation of serotonin neurotransmission can be caused by increased expression of serotonin transporter, which results either from viral infection and subsequent production of interferon–alpha or from abnormal promoter for serotonin transporter gene. Chronic fatigue syndrome and neurotransmitters

Yes, you read that right. The production of interferon-alpha due to a viral infection actually interferes with the genetic transcription of SERT, causing it to overproduce. This downregulates serotonin neurotransmission. Salicylate stimulates serotonin synthesis (the cause of the flavour chemical intolerant’s familiar ‘happy high’), so I suspect it works on CFS in a similar manner, by causing short term rebound deficiencies in substrates due to overproduction, and long-term downregulation of production. I know of several people who have complained of SSRI-like withdrawal symptoms when they begin the failsafe diet.

Serotonin receptor (HTR) polymorphisms are also involved in CFS:

The pathophysiology of CFS remains elusive, although abnormalities in the central nervous system (CNS) have been implicated, particularly hyperactivity of the serotonergic (5-hydroxytryptamine; 5-HT) system and hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Since alterations in 5-HT signaling can lead to physiologic and behavioral changes, a genetic evaluation of the 5-HT system was undertaken to identify serotonergic markers associated with CFS and potential mechanisms for CNS abnormality. A total of 77 polymorphisms in genes related to serotonin synthesis (TPH2), signaling (HTR1A, HTR1E, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR4, HTR5A, HTR6, and HTR7), transport (SLC6A4), and catabolism (MAOA) were examined […] Of the polymorphisms examined, three markers (-1438G/A, C102T, and rs1923884) all located in the 5-HT receptor subtype HTR2A were associated with CFS when compared to NF controls. Additionally, consistent associations were observed between HTR2A variants and quantitative measures of disability and fatigue in all subjects. The most compelling of these associations was with the A allele of -1438G/A (rs6311) which is suggested to have increased promoter activity in functional studies. Further, in silico analysis revealed that the -1438 A allele creates a consensus binding site for Th1/E47, a transcription factor implicated in the development of the nervous system. Electrophoretic mobility shift assay supports allele-specific binding of E47 to the A allele but not the G allele at this locus. These data indicate that sequence variation in HTR2A, potentially resulting in its enhanced activity, may be involved in the pathophysiology of CFS. Genetic evaluation of the serotonergic system in chronic fatigue syndrome

Proopiomelanocortin (POMC), nuclear receptor subfamily 3, group C, member 1 (NR3C1), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and tryptophan hydroxylase 2 (TPH2) polymorphisms are all associated with CFS:

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. […] 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. Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue

Catechol-O-methyltransferase (COMT) polymorphisms, along with some genes already listed above, are associated with CFS:

This paper asks whether the presence of chronic fatigue syndrome (CFS) can be more accurately predicted from single nucleotide polymorphism (SNP) profiles than would occur by chance. […] The top three genes containing the SNPs accounting for the highest accumulated importances were neuronal tryptophan hydroxylase (TPH2), catechol-O-methyltransferase (COMT) and nuclear receptor subfamily 3, group C, member 1 glucocorticoid receptor (NR3C1). CONCLUSION: The fact that only 28 out of several million possible SNPs predict whether a person has CFS with 76% accuracy indicates that CFS has a genetic component that may help to explain some aspects of the illness. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome

Wait. Let’s read that again: only twenty eight out of several million genetic polymorphisms predict whether a person has CFS with a 76% accuracy.

Yasko tests for some of the common polymorphisms listed above: ACE, MAO-A, and COMT. She doesn’t test for CBG, 5-HTT/SERT, POMC, NR3C1, MAO-B or TPH2.

You know you’re on to something when you can predict the genes that are involved in particular illnesses. Though Yasko doesn’t test for POMC variants, we’ve actually been discussing POMC on FailsafeNT recently. It is probably one of the primary genetic components of opioid sensitivity and pain perception. Also, I’ve also been puzzled for a while as to why Yasko doesn’t test for SERT polymorphisms, particularly as serotonin promotes sociability and for this reason is thought to be lacking in some autistics.

Of course, fibromyalgia is very closely related to CFS:

The exposure of a genetically predisposed individual to a host of environmental stressors is presumed to lead to the development of FMS. Fibromyalgia overlaps with several related syndromes, collectively compromising the spectrum of the functional somatic disorder. FMS is characterized by a strong familial aggregation. Recent evidence suggests a role for polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems in the etiopathogenesis of FMS. These polymorphisms are not specific for FMS and are similarly associated with additional comorbid conditions. The mode of inheritance in FMS is unknown, but it is most probably polygenic. Recognition of these gene polymorphisms may help to better subgroup FMS patients and to guide a more rational pharmacological approach. The genetics of fibromyalgia syndrome

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Written by alienrobotgirl

31 January, 2008 at 6:46 pm

Posted in The Genetics of FCI?

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