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

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 controls. Results demonstrate that the COMT rs4680 (val158met) 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 two 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 two 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, while 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.

ENPP1 and ESR1 genotypes influence temporomandibular disorders development and surgical treatment response in dentofacial deformities

“…However, they were many SNPs correlated with intermediate phenotypes TMD (Slade et al, 2013; Smith et al, 2011, 2013). On the other hand, polymorphisms of COMT genes, ESR1 genes and GCH1 genes interact to influence the enzymatic activity of catechol-O-methyltransferase, musculoskeletal pain, and mood constituting a phenomenon of epistasis (Smith et al, 2014). The study of CACNA2D1, a gene of interest in the cohort Oppera encoding subunit alpha-2 / delta-1 of voltage dependent calcium channels implicated in neuropathic pain, has a differential expression in the masseter muscles according and sex between women with or without TMD myalgia-type (Godel et al, 2014; Sciote et al, 2015).…”

Alternative Splicing of G Protein–Coupled Receptors: Relevance to Pain Management

“…Human genetic association studies have shown that the rs4680 SNP, alone or in combination with other nearby SNPs, is predictive of temporomandibular disorder (TMD) and fibromyalgia onset 107,108 . Subsequent molecular studies demonstrated that these SNPs alter the thermostability and/or structure of the COMT transcript 109 , explaining why patients with functional pain disorders 110–112 and exacerbated postoperative pain 113–116 exhibit decreased levels of COMT alongside increased levels of catecholamines. Preclinical studies further revealed that elevated levels of epinephrine/norepinephrine resulting from low COMT activity, lead to increased pain through activation of βARs 117,118 .…”

Persistent Catechol-O-methyltransferase–dependent Pain Is Initiated by Peripheral β-Adrenergic Receptors

“…Patients exhibit increased levels of catecholamines 9-11 alongside diminished activity of catechol-O-methyltransferase (COMT), 12,13 a ubiquitously expressed enzyme that metabolizes catecholamines to their inactive derivatives. 14 Furthermore, functional variants in the COMT gene that reduce COMT activity 13,15,16 are associated with increased susceptibility to FM, 17-21 TMD 22 and experimental pain 22,23 as well as impaired response to treatment. 24,25 It is estimated, based on the frequency of allele variation, that nearly two-thirds of patients with chronic pain disorders possess the low-activity COMT variants.…”