COMT – American ME and CFS Society

Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome

Abstract:

Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function.

A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2500 fewer steps compared with placebo (Pinteraction=0.04).

There were no differences between clonidine and placebo among patients with COMT low-activity alleles. Similar gene-drug interactions were observed for sleep (Pinteraction=0.003) and quality of life (Pinteraction=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine-COMT interaction effects in other conditions

Source: Hall KT, Kossowsky J, Oberlander TF, Kaptchuk TJ, Saul JP, Wyller VB, Fagermoen E, Sulheim D, Gjerstad J, Winger A, Mukamal KJ. Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome. Pharmacogenomics J. 2016 Oct;16(5):454-60. doi: 10.1038/tpj.2016.53. Epub 2016 Jul 26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028250/ (Full article)

Polymorphism in COMT is associated with IgG3 subclass level and susceptibility to infection in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is considered as a neuroimmunological disease but the etiology and pathophysiology is poorly understood. Patients suffer from sustained exhaustion, cognitive impairment and an increased sensitivity to pain and sensory stimuli. A subset of patients has frequent respiratory tract infections (RRTI). Dysregulation of the sympathetic nervous system and an association with genetic variations in the catechol-O-methyltransferase (COMT) and glucocorticoid receptor genes influencing sympathetic and glucocorticoid metabolism were reported in CFS. Here, we analyzed the prevalence of SNPs of COMT and glucocorticoid receptor-associated genes in CFS patients and correlated them to immunoglobulin levels and susceptibility to RRTI.

METHODS: We analyzed blood cells of 74 CFS patients and 76 healthy controls for polymorphisms in COMT, FKBP5 and CRHR1 by allelic discrimination PCR. Serum immunoglobulins were determined by immunoturbidimetric technique, cortisol levels by ECLIA.

RESULTS: Contrary to previous reports, we found no difference between CFS patients and healthy controls in the prevalence of SNPs for COMT, FKBP5 and CRHR1. In patients with the Met/Met variant of COMT rs4680 we observed enhanced cortisol levels providing evidence for its functional relevance. Both enhanced IgE and diminished IgG3 levels and an increased susceptibility to RRTI were observed in CFS patients with the Met/Met variant. Such an association was not observed in 68 non-CFS patients with RRTI.

CONCLUSION: Our results indicate a relationship of COMT polymorphism rs4680 with immune dysregulation in CFS providing a potential link for the association between stress and infection susceptibility in CFS.

Source: Löbel M, Mooslechner AA, Bauer S, Günther S, Letsch A, Hanitsch LG, Grabowski P, Meisel C, Volk HD, Scheibenbogen C. Polymorphism in COMT is associated with IgG3 subclass level and susceptibility to infection in patients with chronic fatigue syndrome. J Transl Med. 2015 Aug 14;13:264. doi: 10.1186/s12967-015-0628-4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536662/ (Full article)

Polymorphisms of adrenergic cardiovascular control genes are associated with adolescent chronic fatigue syndrome

Abstract:

AIM: To explore the frequency of polymorphisms in adrenergic cardiovascular control genes in adolescent with chronic fatigue syndrome (CFS) and the relation of such polymorphisms to cardiovascular variables.

METHODS: DNA from 53 patients with CFS, 12-18 years old, was analysed for five single nucleotide polymorphisms (SNPs) in the genes catechol-O-methyltransferase (COMT), the β₂ -adrenergic receptor (two SNPs), the β₁ -adrenergic receptor and the α₂(a) -adrenergic receptor. Frequencies were compared to a reference population constructed from the National Center for Biotechnology Information (NCBI) database, and associations between frequencies and autonomic cardiovascular responses during a 20° head-up tilt-test were explored.

RESULTS: For the COMT SNP Rs4680, patients with CFS had a higher frequency of the AA genotype and a lower frequency of the G containing genotypes (AG and GG), when compared to the reference sample (p = 0.046). Also, the AA genotype was associated with a smaller increase in LF/HF ratio (low-frequency:high-frequency heart rate variability ratio, an index of cardiac sympathovagal balance) during head-up tilt when compared to the AG/GG genotypes. For the β₂ -adrenergic receptor SNP Rs1042714, patients with CFS had a lower frequency of the GG genotype and a higher frequency of the genotypes containing C (CG and CC) (p = 0.044).

CONCLUSIONS: CFS might be related to polymorphisms of COMT and the β₂ -adrenergic receptor. More details of the molecular mechanisms remain to be investigated.

Source: Sommerfeldt L, Portilla H, Jacobsen L, Gjerstad J, Wyller VB. Polymorphisms of adrenergic cardiovascular control genes are associated with adolescent chronic fatigue syndrome. Acta Paediatr. 2011 Feb;100(2):293-8. doi: 10.1111/j.1651-2227.2010.02072.x. Epub 2010 Nov 18. https://www.ncbi.nlm.nih.gov/pubmed/21059181