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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 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.

SUBMITTER: Smith SB

PROVIDER: S-EPMC4253645 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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

Smith Shad B SB Reenilä Ilkka I Männistö Pekka T PT Slade Gary D GD Maixner William W Diatchenko Luda L Nackley Andrea G AG

Pain 20140916 11

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 am ...[more]

PMID: 25218601

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Project description:BackgroundThe COMT gene polymorphism is associated with neurological and psychiatric disorders and pain perception. The present study investigates the existence of anxiety and pain perception in relation to the COMT (catechol-O-methyltransferase) gene polymorphism in labouring women (during "natural" childbirth) with or without inhaled analgesia.MethodsA total of 181 women who chose vaginal birth were enrolled in this study. To present the difference in pain perception, the parturients were divided into one group (n = 90) that chose labour analgesia with inhaled nitrous oxide (50% nitrous oxide and 50% oxygen) and one group (n = 91) without analgesia. The blood samples were taken during the pregnancy as a part of routine pregnancy controls in the hospital. The COMT gene polymorphism was detected with the PCR technique. The pain perception of parturients was self-evaluated two times according to the VAS (Visual Analogue Scale), and anxiety as a personality trait was determined with the STAI-T (State Trait Anxiety Inventory). Pain perception as well as anxiety were compared according to COMT genotypes.ResultsIn the 181 pregnant women, there were 40 women (22%) of wild homozygotes (GG) of COMT, 95 women (53%) of mutant heterozygotes (GA), and 46 women (25%) of mutant homozygotes (AA). A negative association of pain perception with the GA (mutant heterozygote) polymorphism of the COMT gene versus the wild-type (GG polymorphism) was observed. The GA polymorphism of the COMT gene was associated with 0.46 units lower pain perception compared to the wild type (GG). The anxiety trait score in group AA was lower than in groups GA and GG. The difference reached statistical significance only when comparing AA versus GA (p > 0.042). Analgesic efficacy of nitrous oxide was noticed in 22% of labouring women who reported moderate pain (VAS score 4-7).ConclusionsThe COMT gene polymorphism was associated with pain perception and anxiety among parturients. The COMT gene polymorphism GA was associated with negative pain perception among labouring women. Nitrous oxide showed statistical significance in anxiolytic efficacy during labour in women with mild anxiety as a personality trait. Anxiolytic efficacy of nitrous oxide has shown better efficacy in parturients with the COMT gene polymorphism AA.

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

Publications

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

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