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Low Enzymatic Activity Haplotypes of the Human Catechol-O-Methyltransferase Gene: Enrichment for Marker SNPs  [PDF]
Andrea G. Nackley, Svetlana A. Shabalina, Jason E. Lambert, Mathew S. Conrad, Dustin G. Gibson, Alexey N. Spiridonov, Sarah K. Satterfield, Luda Diatchenko
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005237
Abstract: Catechol-O-methyltransferase (COMT) is an enzyme that plays a key role in the modulation of catechol-dependent functions such as cognition, cardiovascular function, and pain processing. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous (val158met) position, designated as low (LPS), average (APS), and high pain sensitive (HPS), are associated with experimental pain sensitivity and risk of developing chronic musculoskeletal pain conditions. APS and HPS haplotypes produce significant functional effects, coding for 3- and 20-fold reductions in COMT enzymatic activity, respectively. In the present study, we investigated whether additional minor single nucleotide polymorphisms (SNPs), accruing in 1 to 5% of the population, situated in the COMT transcript region contribute to haplotype-dependent enzymatic activity. Computer analysis of COMT ESTs showed that one synonymous minor SNP (rs769224) is linked to the APS haplotype and three minor SNPs (two synonymous: rs6267, rs740602 and one nonsynonymous: rs8192488) are linked to the HPS haplotype. Results from in silico and in vitro experiments revealed that inclusion of allelic variants of these minor SNPs in APS or HPS haplotypes did not modify COMT function at the level of mRNA folding, RNA transcription, protein translation, or enzymatic activity. These data suggest that neutral variants are carried with APS and HPS haplotypes, while the high activity LPS haplotype displays less linked variation. Thus, both minor synonymous and nonsynonymous SNPs in the coding region are markers of functional APS and HPS haplotypes rather than independent contributors to COMT activity.
The Catechol-O-Methyltransferase (COMT) val158met Polymorphism Affects Brain Responses to Repeated Painful Stimuli  [PDF]
Marco L. Loggia, Karin Jensen, Randy L. Gollub, Ajay D. Wasan, Robert R. Edwards, Jian Kong
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027764
Abstract: Despite the explosion of interest in the genetic underpinnings of individual differences in pain sensitivity, conflicting findings have emerged for most of the identified “pain genes”. Perhaps the prime example of this inconsistency is represented by catechol-O-methyltransferase (COMT), as its substantial association to pain sensitivity has been reported in various studies, but rejected in several others. In line with findings from behavioral studies, we hypothesized that the effect of COMT on pain processing would become apparent only when the pain system was adequately challenged (i.e., after repeated pain stimulation). In the present study, we used functional Magnetic Resonance Imaging (fMRI) to investigate the brain response to heat pain stimuli in 54 subjects genotyped for the common COMT val158met polymorphism (val/val = n 22, val/met = n 20, met/met = n 12). Met/met subjects exhibited stronger pain-related fMRI signals than val/val in several brain structures, including the periaqueductal gray matter, lingual gyrus, cerebellum, hippocampal formation and precuneus. These effects were observed only for high intensity pain stimuli after repeated administration. In spite of our relatively small sample size, our results suggest that COMT appears to affect pain processing. Our data demonstrate that the effect of COMT on pain processing can be detected in presence of 1) a sufficiently robust challenge to the pain system to detect a genotype effect, and/or 2) the recruitment of pain-dampening compensatory mechanisms by the putatively more pain sensitive met homozygotes. These findings may help explain the inconsistencies in reported findings of the impact of COMT in pain regulation.
The impact of the Catechol-O-methyltransferase Val158Met polymorphism on survival in the general population – the HUNT study
Knut Hagen, Lars J Stovner, Frank Skorpen, Elin Pettersen, John-Anker Zwart
BMC Medical Genetics , 2007, DOI: 10.1186/1471-2350-8-34
Abstract: The sample comprised 2979 non-diabetic individuals who participated in the Nord-Tr?ndelag Health Study (HUNT) in the period 1995–97. The subjects were followed up with respect to mortality throughout year 2004.212 men and 183 women died during the follow up. No association between codon 158 COMT gene polymorphism and survival was found. The unadjusted relative risk of death by non-ischemic heart diseases with Met/Met or Met/Val genotypes was 3.27 (95% confidence interval, 1.19–9.00) compared to Val/Val genotype. When we adjusted for age, gender, smoking, coffee intake and body mass index the relative risk decreased to 2.89 (95% confidence interval, 1.04–8.00).During 10 year of follow-up, the Val158Met polymorphism had no impact on survival in a general population. Difference in mortality rates from non-ischemic heart diseases may be incidental and should be evaluated in other studies.The catechol-O-methyltransferase (COMT) gene located at chromosome 22q11.2 contains a functional polymorphism at codon 158 that has been the subject of several molecular epidemiological studies because of the important role of the COMT enzyme in the metabolism of catecholamines and catechol estrogens. A substitution of valine (Val) by methionine (Met) at codon 158 affects the activity of the COMT enzyme, and individuals with the Val/Val genotype have a three- to fourfold higher activity of the COMT enzyme than those with Met/Met genotype [1].The Val158Met polymorphism has been linked to e.g. psychiatric disorders and pain perception [2-4], and several epidemiological studies have also reported an association to several potential fatal disorders. Presence of the Val/Val genotype has been considered to be favorable because it seems to lower the risk of developing non-Hodgkin lymphoma and estrogen-associated cancers in women [5-7], and because it is associated with a higher tendency to remain free from increase in prostate-specific antigen in men with prostate cancer [8]. Men with Val/Val
No association between chronic musculoskeletal complaints and Val158Met polymorphism in the Catechol-O-methyltransferase gene. The HUNT study
Knut Hagen, Elin Pettersen, Lars Stovner, Frank Skorpen, John-Anker Zwart
BMC Musculoskeletal Disorders , 2006, DOI: 10.1186/1471-2474-7-40
Abstract: In the 1995–97 Nord-Tr?ndelag Health Study (HUNT), the association between Val/Met polymorphism at the COMT gene and chronic musculoskeletal complaints (MSCs) was evaluated in a random sample of 3017 individuals.The distribution of the COMT Val158Met genotypes and alleles were similar between controls and the twelve different chronic MSCs groups. Even when the Met/Met and Val/Met genotypes were pooled, the distribution of the Val/Val genotype and other genotypes were similar between controls and the chronic MSCs groups.In this population-based study, no significant association was found between Val/Met polymorphism at the COMT gene and chronic MSCs.Musculoskeletal complaints (MSCs), a major health problem worldwide [1,2], probably has a multifactorial etiology and genetic factors may be involved. Recently, a relationship between pain sensitivity and a polymorphism at codon 158 in the Catechol-O-methyltransferase (COMT) gene has been found [3]. COMT is an enzyme which inactivates catecholamines and catechol-containing drugs, and a substitution of valine (Val) by methionine (Met) affects the activity of the COMT enzyme. Individuals with the Val/Val genotype have a three- to fourfold higher activity of the COMT enzyme and reduced pain sensitivity as compared to those with Met/Met genotype [3]. In accordance with this, case-control studies have found that migraine [4] and fibromyalgia [5] were less frequent among those with the Val/Val genotype.In this population-based study performed among unselected adults we evaluated the relationship between Val/Met polymorphism at the COMT gene and chronic MSCs.Between August 1995 and June 1997, all inhabitants aged 20 years and older in Nord-Tr?ndelag county in Norway (n = 92,936) were invited to participate in the Nord-Tr?ndelag Health Survey ("Helseunders?kelsen i Nord-Tr?ndelag"= HUNT). In brief, two questionnaires including > 200 health-related questions were administrated to the participants. The first questionnaire (Q1) was
The Relationship between the Val158Met Catechol-o-Methyltransferase (COMT) Polymorphism and Irritable Bowel Syndrome  [PDF]
Pontus Karling,?ke Danielsson,Mikael Wikgren,Ingegerd S?derstr?m I,Jurgen Del-Favero,Rolf Adolfsson,Karl-Fredrik Norrback
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018035
Abstract: The catechol-O-methyltransferase (COMT) enzyme has a key function in the degradation of catecholamines and a functional polymorphism is val158met. The val/val genotype results in a three to fourfold higher enzymatic activity compared with the met/met genotype, with the val/met genotype exhibiting intermediate activity. Since pain syndromes as well as anxiety and depression are associated to low and high COMT activity respectively and these conditions are all associated with irritable bowel syndrome (IBS) we wanted for the first time to explore the relationship between the polymorphism and IBS.
Depression and anxiety in relation to catechol-O-methyltransferase Val158Met genotype in the general population: The Nord-Tr?ndelag Health Study (HUNT)
Petter M B?kken, Frank Skorpen, Eystein Stordal, John-Anker Zwart, Knut Hagen
BMC Psychiatry , 2008, DOI: 10.1186/1471-244x-8-48
Abstract: In the Nord-Tr?ndelag Health Study (HUNT) the association between the Val158Met polymorphism and anxiety and depression was evaluated in a random sample of 5531 individuals. Two different cut off scores (≥ 8 and ≥ 11) were used to identify cases with anxiety (HADS-A) and depression (HADS-D), whereas controls had HADS-A <8 and HADS-D <8.The COMT genotype distribution was similar between controls and individuals in the groups with anxiety and depression using cut-off scores of ≥ 8. When utilizing the alternative cut-off score HADS-D ≥ 11, Met/Met genotype and Met allele were less common among men with depression compared to the controls (genotype: p = 0.017, allele: p = 0.006). In the multivariate analysis, adjusting for age and heart disease, depression (HADS-D ≥ 11) was less likely among men with the Met/Met genotype than among men with the Val/Val genotype (OR = 0.37, 95% CI = 0.18–0.76).In this population-based study, no clear association between the Val158Met polymorphism and depression and anxiety was revealed. The Met/Met genotype was less likely among men with depression defined as HADS-D ≥ 11, but this may be an incidental finding.The catechol-O-methyltransferase (COMT) gene located on chromosome 22q11.2 contains a common functional polymorphism at codon 158. This polymorphism has been subject to a large number of studies, due to the COMT enzyme's important role in the metabolism of catecholamines (1). A substitution of valine (Val) by methionine (Met) at codon 158 affects the activity of the COMT enzyme, and individuals with the Val/Val genotype have a 3–4-times higher enzyme activity than those with the Met/Met genotype [1]. Since the alleles are co-dominant, heterozygous individuals (Val/Met) show an enzyme activity halfway between the homozygous genotypes.The Val158Met polymorphism has been linked to a broad range of psychiatric disorders including anxiety and mood disorders [2]. Although anxiety and depression both are influenced by several genes in comb
How large should the QM region be in QM/MM calculations? The case of catechol O-methyltransferase  [PDF]
Heather J. Kulik,Jianyu Zhang,Judith P. Klinman,Todd J. Martinez
Quantitative Biology , 2015,
Abstract: Hybrid quantum mechanical-molecular mechanical (QM/MM) simulations are widely used in studies of enzymatic catalysis. Up until now, it has usually been cost prohibitive to determine the convergence of these calculations with respect to the size of the QM region. Recent advances in reformulating electronic structure algorithms for stream processors such as graphical processing units have made QM/MM calculations of optimized reaction paths with QM regions comprising up to O(10^3) atoms feasible. Here, we leverage these GPU-accelerated quantum chemistry methods to investigate catalytic properties in catechol O-methyltransferase. Using QM regions ranging in size from the reactant only (63 atoms) up to nearly one-third of the entire protein (940 atoms), we show that convergence of properties such as the activation energy of the catalyzed reaction can be quite slow. Convergence to within chemical accuracy for this case requires a quantum mechanical region with approximately 500 atoms. These results call for a more careful determination of QM region sizes in future QM/MM studies of enzymes.
Catechol-O-methyltransferase and Parkinson's disease.
Tai CH,Wu RM
Acta Medica Okayama , 2002,
Abstract: Parkinson's disease (PD) is one of the main causes of neurological disability in the elderly. Levodopa is the gold standard for treating this disease, but chronic levodopa therapy is complicated by motor fluctuation and dyskinesia. The catechol-O-methyltransferase (COMT) inhibitors represent a new class of antiparkinsonian drugs. When coadministered with levodopa/decarboxylase inhibitor, 2 COMT inhibitors, tolcapone and entacapone have been shown to improve the clinical benefit of levodopa. COMT activity is genetically polymorphic, and individuals with the low activity (COMT(L/L)) genotype have a thermolabile COMT protein; studies suggest that this genotype is less common in Asians than in Caucasians. Differences in COMT activity may determine the individual response to levodopa and result in ethnic differences in PD susceptibility. Our recent study suggests that the COMTL allele can interact with the MAOB gene to increase the occurrence of PD in Taiwanese. In order to understand this new class of antiparkinsonian drugs, we review their basic properties, pharmacology, and clinical efficacy. The frequency distribution of COMT genetic polymorphisms among different populations and its implications in the etiology and drug response is also discussed.
Hypnotizability and Catechol-O-Methyltransferase (COMT) polymorphysms in Italians  [PDF]
Alessandro Gialluisi,Enrica L. Santarcangelo
Frontiers in Human Neuroscience , 2014, DOI: 10.3389/fnhum.2013.00929
Abstract: Higher brain dopamine content depending on lower activity of Catechol-O-Methyltransferase (COMT) in subjects with high hypnotizability scores (highs) has been considered responsible for their attentional characteristics. However, the results of the previous genetic studies on association between hypnotizability and the COMT single nucleotide polymorphism (SNP) rs4680 (Val158Met) were inconsistent. Here, we used a selective genotyping approach to re-evaluate the association between hypnotizability and COMT in the context of a two-SNP haplotype analysis, considering not only the Val158Met polymorphism, but also the closely located rs4818 SNP. An Italian sample of 53 highs, 49 low hypnotizable subjects (lows), and 57 controls, were genotyped for a segment of 805 bp of the COMT gene, including Val158Met and the closely located rs4818 SNP. Our selective genotyping approach had 97.1% power to detect the previously reported strongest association at the significance level of 5%. We found no evidence of association at the SNP, haplotype, and diplotype levels. Thus, our results challenge the dopamine-based theory of hypnosis and indirectly support recent neuropsychological and neurophysiological findings reporting the lack of any association between hypnotizability and focused attention abilities.
Genetic variation in the Catechol-O-Methyltransferase (COMT) gene and morphine requirements in cancer patients with pain
Trude T Rakv?g, Joy R Ross, Hiroe Sato, Frank Skorpen, Stein Kaasa, P?l Klepstad
Molecular Pain , 2008, DOI: 10.1186/1744-8069-4-64
Abstract: We genotyped 11 single nucleotide polymorphisms (SNPs) throughout the COMT gene, and constructed haplotypes from these 11 SNPs, which were in Hardy-Weinberg equilibrium. We compared both genotypes and haplotypes against pharmacological, demographical and patient symptoms measurements in a Caucasian cancer patient cohort (n = 197) receiving oral morphine treatment for cancer pain. There were two frequent haplotypes (34.5% and 17.8%) in our cohort. Multivariate analyses showed that patients carrying the most frequent haplotype (34.5%) needed lower morphine doses than patients not carrying the haplotype, with a reduction factor of 0.71 (p = 0.005). On the allele level, carriers of alleles for six of the SNPs show weak associations in respect to morphine dose and the alleles associated with the lowest morphine doses constitute part of the most frequent haplotype.This study suggests that genetic variability in the COMT gene influence the efficacy of morphine in cancer patients with pain, and that increased understanding of this variability is reached by expanding from analyses of single SNPs to haplotype construction and analyses.One of the genes in which variability is believed to contribute to differences in pain sensitivity and response to analgesics is the catechol-O-methyltransferase (COMT) gene [1-3]. The COMT enzyme metabolises catecholamines such as dopamine, noradrenaline and adrenaline. The most studied single nucleotide polymorphism (SNP) in the COMT gene is the Rs4680, also known as Val158Met. This polymorphism causes a substitution from a valine (Val) to a methionine (Met) at amino acid position 158, leading to a three- to four-fold reduced activity of the COMT enzyme [4]. Because of the influence on COMT activity by the Rs4680 (Val158Met) SNP and the well established involvement of catecholamines in pain perception [5-7], several studies have investigated if this SNP can explain interindividual variability in pain perception and efficacy of analgesics. Zubi
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