Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease

Caroline Moreau, Sayah Meguig, Jean Christophe Corvol, Julien Labreuche, Francis Vasseur, Alain Duhamel, Arnaud Delval, Thomas Bardyn, Jean Christophe Devedjian, Nathalie Rouaix, Gregory Petyt, Christine Brefel-Courbon, Fabienne Ory-Magne, Dominique Guehl, Alexandre Eusebio, Valérie Fraix, Pierre Jean Saulnier, Ouhaid Lagha-Boukbiza, Frank Durif, Mirela Faighel & 16 others Caroline Giordana, Sophie Drapier, David Maltête, Christine Tranchant, Jean Luc Houeto, Bettina Debû, Jean Philippe Azulay, François Tison, Alain Destée, Marie Vidailhet, Olivier Rascol, Kathy Dujardin, Luc Defebvre, Régis Bordet, Bernard Sablonnière, David Devos

Research output: Contribution to journalArticle

Abstract

After more than 50 years of treating Parkinson's disease with l-DOPA, there are still no guidelines on setting the optimal dose for a given patient. The dopamine transporter type 1, now known as solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3) is the most powerful determinant of dopamine neurotransmission and might therefore influence the treatment response. We recently demonstrated that methylphenidate (a dopamine transporter inhibitor) is effective in patients with Parkinson's disease with motor and gait disorders. The objective of the present study was to determine whether genetic variants of the dopamine transporter type 1-encoding gene (SLC6A3) are associated with differences in the response to treatment of motor symptoms and gait disorders with l-DOPA and methylphenidate (with respect to the demographic, the disease and the treatment parameters and the other genes involved in the dopaminergic neurotransmission). This analysis was part of a multicentre, parallel-group, double-blind, placebo-controlled, randomized clinical trial of methylphenidate in Parkinson's disease (Protocol ID:2008-005801-20; ClinicalTrials.gov:NCT00914095). We scored the motor Unified Parkinson's Disease Rating Scale and the Stand-Walk-Sit Test before and after a standardized acute l-DOPA challenge before randomization and then after 3 months of methylphenidate treatment. Patients were screened for variants of genes involved in dopamine metabolism: rs28363170 and rs3836790 polymorphisms in the SLC6A3 gene, rs921451 and rs3837091 in the DDC gene (encoding the aromatic L-amino acid decarboxylase involved in the synthesis of dopamine from l-DOPA), rs1799836 in the MAOB gene (coding for monoamine oxidase B) and rs4680 in the COMT gene (coding for catechol-O-methyltransferase). Investigators and patients were blinded to the genotyping data throughout the study. Eighty-one subjects were genotyped and 61 were analysed for their acute motor response to l-DOPA. The SLC6A3 variants were significantly associated with greater efficacy of l-DOPA for motor symptoms. The SLC6A3 variants were also associated with greater efficacy of methylphenidate for motor symptoms and gait disorders in the ON l-DOPA condition. The difference between motor Unified Parkinson's Disease Rating Scale scores for patients with different SLC6A3 genotypes was statistically significant in a multivariate analysis that took account of other disease-related, treatment-related and pharmacogenetic parameters. Our preliminary results suggest that variants of SLC6A3 are genetic modifiers of the treatment response to l-DOPA and methylphenidate in Parkinson's disease. Further studies are required to assess the possible value of these genotypes for (i) guiding l-DOPA dose adaptations over the long term; and (ii) establishing the risk/benefit balance associated with methylphenidate treatment for gait disorders.

Original languageEnglish (US)
Pages (from-to)1271-1283
Number of pages13
JournalBrain
Volume138
Issue number5
DOIs
StatePublished - May 1 2015
Externally publishedYes

Fingerprint

Dopamine Plasma Membrane Transport Proteins
Methylphenidate
Parkinson Disease
Gait
Genes
Dopamine
Synaptic Transmission
Therapeutics
Neurotransmitter Transport Proteins
Genotype
Aromatic-L-Amino-Acid Decarboxylases
Catechol O-Methyltransferase
Pharmacogenetics
Monoamine Oxidase
Random Allocation
Gene
Polymorphism
Parkinson's Disease
Multivariate Analysis
Randomized Controlled Trials

Keywords

  • cognitive disorders
  • levodopa
  • methylphenidate
  • Parkinson's disease
  • pharmacogenetics

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)
  • Medicine(all)

Cite this

Moreau, C., Meguig, S., Corvol, J. C., Labreuche, J., Vasseur, F., Duhamel, A., ... Devos, D. (2015). Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease. Brain, 138(5), 1271-1283. https://doi.org/10.1093/brain/awv063

Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease. / Moreau, Caroline; Meguig, Sayah; Corvol, Jean Christophe; Labreuche, Julien; Vasseur, Francis; Duhamel, Alain; Delval, Arnaud; Bardyn, Thomas; Devedjian, Jean Christophe; Rouaix, Nathalie; Petyt, Gregory; Brefel-Courbon, Christine; Ory-Magne, Fabienne; Guehl, Dominique; Eusebio, Alexandre; Fraix, Valérie; Saulnier, Pierre Jean; Lagha-Boukbiza, Ouhaid; Durif, Frank; Faighel, Mirela; Giordana, Caroline; Drapier, Sophie; Maltête, David; Tranchant, Christine; Houeto, Jean Luc; Debû, Bettina; Azulay, Jean Philippe; Tison, François; Destée, Alain; Vidailhet, Marie; Rascol, Olivier; Dujardin, Kathy; Defebvre, Luc; Bordet, Régis; Sablonnière, Bernard; Devos, David.

In: Brain, Vol. 138, No. 5, 01.05.2015, p. 1271-1283.

Research output: Contribution to journalArticle

Moreau, C, Meguig, S, Corvol, JC, Labreuche, J, Vasseur, F, Duhamel, A, Delval, A, Bardyn, T, Devedjian, JC, Rouaix, N, Petyt, G, Brefel-Courbon, C, Ory-Magne, F, Guehl, D, Eusebio, A, Fraix, V, Saulnier, PJ, Lagha-Boukbiza, O, Durif, F, Faighel, M, Giordana, C, Drapier, S, Maltête, D, Tranchant, C, Houeto, JL, Debû, B, Azulay, JP, Tison, F, Destée, A, Vidailhet, M, Rascol, O, Dujardin, K, Defebvre, L, Bordet, R, Sablonnière, B & Devos, D 2015, 'Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease', Brain, vol. 138, no. 5, pp. 1271-1283. https://doi.org/10.1093/brain/awv063
Moreau, Caroline ; Meguig, Sayah ; Corvol, Jean Christophe ; Labreuche, Julien ; Vasseur, Francis ; Duhamel, Alain ; Delval, Arnaud ; Bardyn, Thomas ; Devedjian, Jean Christophe ; Rouaix, Nathalie ; Petyt, Gregory ; Brefel-Courbon, Christine ; Ory-Magne, Fabienne ; Guehl, Dominique ; Eusebio, Alexandre ; Fraix, Valérie ; Saulnier, Pierre Jean ; Lagha-Boukbiza, Ouhaid ; Durif, Frank ; Faighel, Mirela ; Giordana, Caroline ; Drapier, Sophie ; Maltête, David ; Tranchant, Christine ; Houeto, Jean Luc ; Debû, Bettina ; Azulay, Jean Philippe ; Tison, François ; Destée, Alain ; Vidailhet, Marie ; Rascol, Olivier ; Dujardin, Kathy ; Defebvre, Luc ; Bordet, Régis ; Sablonnière, Bernard ; Devos, David. / Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease. In: Brain. 2015 ; Vol. 138, No. 5. pp. 1271-1283.
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