Dopaminergic denervation severity depends on COMT Val158Met polymorphism in Parkinson's disease

Muellner, Julia; Gharrad, Iman; Habert, Marie‐Odile; Kas, Aurélie; Martini, Jean‐Baptiste; Cormier‐Dequaire, Florence; Tahiri, Khadija; Vidailhet, Marie; Meier, Niklaus; Brice, Alexis; Schuepbach, Michael; Mallet, Alain; Hartmann, Andreas; Corvol, Jean‐Christophe

doi:10.1016/j.parkreldis.2015.02.009

Cited by 17 publications

(12 citation statements)

References 33 publications

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“…We also found increased levels of caudate DAT in Met/Met carriers of COMT polymorphism. This is consistent with a 18 F-DOPA PET study, which found higher presynaptic dopamine levels in frontal regions in Met/Met [26], and in controversy with a recent study that found higher levels of striatal FP-CIT BP in Val/Val [27]. However, this last result could be a false positive due to a small sample size (40 subjects in total, and only 3 Met/Met carriers).…”

Section: Discussionsupporting

confidence: 90%

Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease

et al. 2017

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The dual syndrome hypothesis for cognitive impairment in Parkinson's disease (PD) establishes a dichotomy between a frontrostriatal dopamine-mediated syndrome, which leads to executive deficits, and a posterior cortical syndrome, which leads to dementia. Certain genes have been linked to these syndromes although the exact contribution is still controversial. The study’s objective was to investigate the role of APOE, MAPT, COMT, SNCA and GBA genes in the dual syndromes. We genotyped APOE (rs429358 and rs7412), MAPT (rs9468), COMT (rs4680) and SNCA (rs356219) risk polymorphisms and sequenced GBA in a cohort of 298 PD patients. The degree of dopaminergic depletion was investigated with [123I]FP-CIT SPECTs and the presence of dementia was ascertained with a long-term review based on established criteria. The association between genetic and imaging parameters was studied with linear regression, and the relationship with dementia onset with Cox regression. We found that APOE2 allele (Pput = 0.002; Pcau = 0.01), the minor allele 'G' in SNCA polymorphism (Pput = 0.02; Pcau = 0.006) and GBA deleterious variants in (Pput = 0.01; Pcau = 0.001) had a detrimental effect on striatal [123I]FP-CIT uptake in PD. Conversely, Met/Met carriers in COMT polymorphism had increased caudate uptake (Pcau = 0.03). The development of dementia was influenced by APOE4 allele (HR = 1.90; P = 0.03) and GBA deleterious variants (HR = 2.44; P = 0.01). Finally, we observed no role of MAPT locus in any of the syndromes. As a conclusion, APOE2, SNCA, COMT and GBA influence frontostriatal dysfunction whereas APOE4 and GBA influence the development of dementia, suggesting a double-edged role of GBA. The dichotomy of the dual syndromes may be driven by a broad dichotomy in these genetic factors.

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Section: Discussionsupporting

confidence: 90%

Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease

et al. 2017

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“…11 The A allele was associated with a reduction of 3-to 4-fold in the enzyme activity, being designated as L (low activity), whereas the G allele has been called H because it is associated with higher enzymatic activity. 12 In addition, the MAO-B gene contains a single-stranded conformational polymorphism within intron 13 (rs1799836), which results in a transitional conversion of adenine (A) to guanine (G) creating a splicing enhancer, thus changing the enzymatic activity. [13][14][15] The impact of genetic variants in the choice of the more adequate PD treatment is still controversial.…”

mentioning

confidence: 99%

“…The nonsynonym SNP rs4680 in COMT , a G→A transition (valine‐methionine substitution) on codon 158 (exon 4) of the membrane‐bound transcript variant, has been associated with the modulation of enzyme activity . The A allele was associated with a reduction of 3‐ to 4‐fold in the enzyme activity, being designated as L (low activity), whereas the G allele has been called H because it is associated with higher enzymatic activity . In addition, the MAO‐B gene contains a single‐stranded conformational polymorphism within intron 13 (rs1799836), which results in a transitional conversion of adenine (A) to guanine (G) creating a splicing enhancer, thus changing the enzymatic activity …”

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confidence: 99%

MAO‐BandCOMTGenetic Variations Associated With Levodopa Treatment Response in Patients With Parkinson's Disease

Sampaio

Santos

Lima

et al. 2018

The Journal of Clinical Pharma

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The most commonly used Parkinson's disease (PD) treatment is the replacement of dopamine by its levodopa precursor (l-dopa). Monoamine oxidase-B (MAO-B) and catechol-o-methyl transferase (COMT) are enzymes involved in the metabolism and regulation of dopamine availability. In our study we investigated the possible relation among selected single-nucleotide polymorphisms (SNPs) in the MAO-B (rs1799836) and COMT (rs4680) genes and the therapeutic response to levodopa (l-dopa). A total of 162 Brazilian patients from the Pro-Parkinson service of Clinics Hospital of Pernambuco diagnosed with sporadic PD and treated with levodopa were enrolled. PD patients were stratified into 2 groups according to the daily levodopa dose. MAO-B and COMT SNP genotyping was conducted by polymerase chain reaction-restriction fragment length polymorphism. After multivariate analysis, we observed a significant difference between PD groups for the following variables: sex (P = .02), longer duration of disease (P = .02), longer levodopa therapy duration (P = .01), younger onset of PD (P = .01), and use of COMT inhibitor (P = .02). We observed that patients carrying MAO-B (rs1799836) A and AA genotypes and COMT (rs4680) LL genotype suffered more frequently from levodopa-induced-dyskinesia. In addition, we found an increased risk of 2.84-fold for male individuals carrying the MAO-B G allele to be treated with higher doses of levodopa (P = .04). We concluded that before beginning PD pharmacological treatment, it is important to consider the genetic variants of the MAO-B and COMT genes and the sex, reinforcing the evidence that sexual dimorphism in the genes related to dopamine metabolism might affect PD treatment.

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“…Кодирующий метионин аллель А связан со снижением ферментативной активности в 3-4 раза и, как следствие, обусловливает высокое содержание леводопы и дофамина. Кодирующий валин аллель G, напротив, ассоциирован с более высокой активностью фермента, что приводит к быстрому снижению концентрации дофамина в синаптической щели [11]. M. Bialecka и соавт.…”

Section: о б з о р ыunclassified

Pharmacogenetics of drug-induced dyskinesias in Parkinson's disease

Tappakhov

Попова

Govorova

et al. 2020

RJTAO

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В изучении патогенеза болезни Паркинсона (БП) достигнуты большие успехи, определена роль недофаминергических систем мозга в клинической картине заболевания, внедрены нейрохирургические вмешательства на глубинных структурах головного мозга, однако препараты леводопы продолжают оставаться «золотым» стандартом лечения данной патологии [1, 2]. Неизбежным осложне-нием леводопа-терапии является развитие лекарственных дискинезий (ЛД), моторных и немоторных флюктуаций, что значительно ограничивает терапевтические возможности данной группы препаратов, ухудшает качество жизни пациентов и требует корректировки лечения [3-5]. Так, ЛД встречаются примерно у 30% пациентов через 5 лет и у 59-100% через 10 лет после начала леводопа-терапии [6].

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Dopaminergic denervation severity depends on COMT Val158Met polymorphism in Parkinson's disease

Abstract: Striatal denervation differs according to COMT-Val158Met polymorphism. COMT activity may play a role as a compensatory mechanism in PD motor symptoms.

Cited by 17 publications

References 33 publications

Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease

Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease

MAO‐BandCOMTGenetic Variations Associated With Levodopa Treatment Response in Patients With Parkinson's Disease

Pharmacogenetics of drug-induced dyskinesias in Parkinson's disease

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