Polymorphisms of Catechol-O-Methyl Transferase (COMT) Gene in Vulnerability to Levodopa-Induced Dyskinesia

Ivanova, Svetlana A.; Алифирова, В. М.; Pozhidaev, Ivan V; Freidin, Maxim B.; Жукова, И. А.; Osmanova, D.; Жукова, Н. Г.; Mironova, Y.; Tiguntsev, V. V.; Fedorenko, Olga Yu; Бохан, Н. А.; Wilffert, Bob; Loonen, Anton J. M.

doi:10.18433/jpps29903

Cited by 12 publications

(10 citation statements)

References 39 publications

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“…The COMT Val158Met variant is known to be associated with neuropsychiatric disorders such as Attention-Deficit/Hyperactivity Disorder [130], but not with LID in PD patients [131]. This could be related to the difference in expression of DA-transporters in different brain regions [131,132]. We identified only one study of a possible association of variants of the MAOA or MAOB genes with TD [133].…”

Section: Dopaminergic Neuronsmentioning

confidence: 93%

“…Although an association between certain variants of the dopamine catalyzing enzyme COMT gene has been described [115,127,128], meta-analysis have shown that the most important functional COMT Val158Met (rs4680) variant shows very little association with TD [115,128,129]. The COMT Val158Met variant is known to be associated with neuropsychiatric disorders such as Attention-Deficit/Hyperactivity Disorder [130], but not with LID in PD patients [131]. This could be related to the difference in expression of DA-transporters in different brain regions [131,132].…”

Section: Dopaminergic Neuronsmentioning

confidence: 99%

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Putative Role of Pharmacogenetics to Elucidate the Mechanism of Tardive Dyskinesia in Schizophrenia

2019

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Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies.

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Section: Dopaminergic Neuronsmentioning

confidence: 93%

Section: Dopaminergic Neuronsmentioning

confidence: 99%

Putative Role of Pharmacogenetics to Elucidate the Mechanism of Tardive Dyskinesia in Schizophrenia

2019

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“…But on contrary to these studies, Contin et al 9 and Cheshire et al 10 found that prevalence and time of onset of dyskinesia were not influenced by any particular genotype of rs4680 SNP. Similarly, Ivanova et al 11 have shown that rare allele (A) or homozygote for rare allele (AA) were protective against LID, but it does not reach statistical significance when the duration of disease was added as a covariate in regression analysis. So, the studies focussing on SNPs of different genes show conflicting results.…”

Section: Discussionmentioning

confidence: 99%

“…Some studies reported that COMT rs4680 is associated with LID (de Lau et al 2012;Sampaio et al 2018;dos Santos et al 2020;Watanabe et al 2003), while others found no association with LID susceptibility. [9][10][11][12] Conflicting results of these studies might be due to the small sample size, different ethnicity of subjects, different recruiting criteria, and various clinical factors. In the present study, we have used meta-analytic techniques to further our understanding and assess the association of COMT rs4680 polymorphisms with LID in PD.…”

Section: Introductionmentioning

confidence: 99%

Association of Catechol-O-Methyltransferase Gene rs4680 Polymorphism and Levodopa Induced Dyskinesia in Parkinson’s Disease: A Meta-Analysis and Systematic Review

Dwivedi

Kumar

et al. 2022

J Geriatr Psychiatry Neurol

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Introduction Long-term levodopa therapy for Parkinson’s disease (PD) can cause levodopa induced dyskinesia (LID). Genetic predisposition has a significant role to play in inter-individual heterogeneity in the clinical manifestation of LID. Despite accumulating evidence for the role of COMT gene polymorphism (rs4680) as a genetic basis for LID, to date results have been inconsistent. Early assessment of the Catechol-O-Methyltransferase (COMT) genotype might be helpful to stratify PD patients concerning their individual risk for LID. Method In this meta-analysis, we have used 9 studies, which were selected through online databases. Statistical analysis was performed using R (v-3.6) software. 5 genetic models have been used in the present study: Allele model (A vs. G), Dominant model (AA+AG vs. GG), Homozygote model (AA vs. GG), Co-dominant/heterozygote model (AG vs. GG), and Recessive model (AA vs. AG + GG). Results The results indicated a significant association between COMT rs4680 (Val158Met) polymorphism and LID risk. The genotype AA of COMT rs4680 is a risk factor for LID in PD patients under the recessive model (AA vs GG+AG) in the random-effect model. Analysis based on ethnicity showed that COMT rs4680 SNP allele A is a risk factor for LID development in Asian PD patients, while GG genotype is a risk factor for LID development in non-Asian PD patients using different genetic models. Conclusion The results of the present meta-analysis support that the COMT Val158Met polymorphism is a risk factor for the development of LID in PD patients having ethnic variations.

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“…In the Xiao Q 11 study, the authors failed to arrive at the same conclusion because a limited number of patients (only 12.6%) presented with dyskinesia. Recently, Ivanova SA 18 found an association between four SNPs-rs165774, rs4818, rs4633, and rs4680-and L-dopa-induced dyskinesia. However, the results did not reach statistical significance when the duration of disease was added as a covariate in regression analysis, and only the additive model for rs165774 was found to be close to statistical significance.…”

Section: Discussionmentioning

confidence: 99%

Genetic variations in catechol-O-methyltransferase gene are associated with levodopa response variability in Chinese patients with Parkinson’s disease

Zhao

Wang

Zhang

et al. 2020

Sci Rep

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catechol-o-methyltransferase (coMt) is one of the main enzymes in dopamine metabolism and is reported to be associated with susceptibility to parkinson's disease (pD) and pharmacotherapy. However, researchers mostly focus on the most common polymorphism, rs4680. In this case-control study, we investigated the association of SNPs other than rs4680 with the levodopa (L-dopa) response and other clinical features in chinese pD patients. eleven single nucleotide polymorphisms (Snps) in the coMt gene were genotyped, and clinical data were collected. patients with the tt genotype of rs165728 or rs174699 had larger daily levodopa equivalent doses (LEDs) than the patients with CC and ct genotypes under the dominant model (p = 0.01421 for rs165728 and p = 0.02302 for rs174699). Under the dominant model, the patients with GG at rs4680 G > A had a lower occurrence of dyskinesia than those with AA and AG (p = 0.0196). Patients with CC at rs4633 had a lower occurrence of dyskinesia than those with tt and tc (p = 0.0429) under the dominant model. The frequencies of the rs174675 T and rs933271 C alleles were higher in PD patients than in the controls (p < 0.05). Our primary results showed the possible association of SNPs other than the most common functional rs4680 in COMT with interindividual variance in the L-dopa daily dose and susceptibility to dyskinesia in Chinese patients, although this was an exploratory study based on a small sample size. Larger and more randomized samples are necessary for further investigation. Parkinson's disease (PD) is a common progressive age-related neurodegenerative disease with a prevalence from 41/100,000 in people in their 40 s to more than 1900/100,000 in people in their 80s 1. The main chemical marker of PD is the loss of dopamine production because of the progressive loss of dopaminergic neurons in the substantia nigra in the midbrain 2. The dopamine precursor levodopa (L-dopa) remains the mainstay of treatment and has been the most effective symptomatic therapy in PD since its introduction 3,4. In fact, there are considerable inter-individual and intra-individual variations in the response to L-dopa, including motor fluctuations and dyskinesia 3. "Wearing-off " is a predictable recurrence of symptoms ahead of scheduled doses of dopamine medication, and the symptoms improve after the next dose. Dyskinesia is a kind of involuntary movement from mild to severe and potentially affects 30-40% of PD patients treated with L-dopa. The prevalence of "wearing-off " and dyskinesia was 41-55% over 5 years of treatment with L-dopa. It has been reported that pulsatile stimulation of dopamine receptors accounts for the complications involved in L-dopa therapy. Nutt JG 5 reported that 60-90% of the variability in the pharmacokinetics and pharmacodynamics of antiparkinsonian medicine comes from pharmacogenomics. Understanding the pharmacogenetic factors involved in the mechanism, metabolism, transmission and receptors might lead physicians to optimize L-dopa doses and control motor complications 6. Catech...

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Polymorphisms of Catechol-O-Methyl Transferase (COMT) Gene in Vulnerability to Levodopa-Induced Dyskinesia

Cited by 12 publications

References 39 publications

Putative Role of Pharmacogenetics to Elucidate the Mechanism of Tardive Dyskinesia in Schizophrenia

Putative Role of Pharmacogenetics to Elucidate the Mechanism of Tardive Dyskinesia in Schizophrenia

Association of Catechol-O-Methyltransferase Gene rs4680 Polymorphism and Levodopa Induced Dyskinesia in Parkinson’s Disease: A Meta-Analysis and Systematic Review

Genetic variations in catechol-O-methyltransferase gene are associated with levodopa response variability in Chinese patients with Parkinson’s disease

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