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Pain. 2014 Nov;155(11):2390-9. doi: 10.1016/j.pain.2014.09.009. Epub 2014 Sep 16.

Epistasis between polymorphisms in COMT, ESR1, and GCH1 influences COMT enzyme activity and pain.

Author information

1
Center for Pain Research and Innovation, School of Dentistry, University of North Carolina, Chapel Hill, NC, USA.
2
Division of Pharmacology and Toxicology, University of Helsinki, Helsinki, Finland.
3
Center for Pain Research and Innovation, School of Dentistry, University of North Carolina, Chapel Hill, NC, USA; Alan Edwards Pain Centre For Research on Pain, McGill University, Montreal, Canada.
4
Center for Pain Research and Innovation, School of Dentistry, University of North Carolina, Chapel Hill, NC, USA. Electronic address: andrea_nackley@dentistry.unc.edu.

Abstract

Abnormalities in the enzymatic activity of catechol-O-methyltransferase (COMT) contribute to chronic pain conditions, such as temporomandibular disorders (TMD). Thus, we sought to determine the effects of polymorphisms in COMT and functionally related pain genes in the COMT pathway (estrogen receptor 1 [ESR1], guanosine-5-triphosphate cyclohydrolase 1 [GCH1], methylenetetrahydrofolate reductase [MTHFR]) on COMT enzymatic activity, musculoskeletal pain, and pain-related intermediate phenotypes among TMD cases and healthy control subjects. Results show that the COMT rs4680 (val(158)met) polymorphism is most strongly associated with outcome measures, such that individuals with the minor A allele (met) exhibit reduced COMT activity, increased TMD risk, and increased musculoskeletal pain. Epistatic interactions were observed between the COMT rs4680 polymorphism and polymorphisms in GCH1 and ESR1. Among individuals with the COMT met allele, those with 2 copies of the GCH1 rs10483639 minor G allele exhibit normalized COMT activity and increased mechanical pain thresholds. Among individuals with the COMT val allele, those with 2 copies of the ESR1 rs3020377 minor A allele exhibit reduced COMT activity, increased bodily pain, and poorer self-reported health. These data reveal that the GCH1 minor G allele confers a protective advantage among met carriers, whereas the ESR1 minor A allele is disadvantageous among val carriers. Furthermore, these data suggest that the ability to predict the downstream effects of genetic variation on COMT activity is critically important to understanding the molecular basis of chronic pain conditions.

KEYWORDS:

Catecholamines; Fibromyalgia; Gene expression; Gene–gene interaction; Temporomandibular disorders

PMID:
25218601
PMCID:
PMC4253645
DOI:
10.1016/j.pain.2014.09.009
[Indexed for MEDLINE]
Free PMC Article

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