title: Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease.
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.
authors: 1 Department of Movement Disorders and Neurology, Lille University, CHU Lille, Lille, France 2 INSERM U1171, Lille University, Lille, France.
authors: Caroline
authors: C
authors: Moreau
authors: 3 Department of Molecular Biology and Pathology Centre, Lille University, CHU Lille, Lille, France.
authors: Sayah
authors: S
authors: Meguig
authors: 4 Sorbonne Universités, UPMC Univ Paris 06, and INSERM UMRS_1127 and CIC_1422, and CNRS UMR_7225, and AP-HP, and ICM, Hôpital Pitié-Salpêtrière, Département des Maladies du Système Nerveux, Paris, France.
authors: Jean-Christophe
authors: JC
authors: Corvol
authors: 5 Department of Biostatistics, Lille University, CHU Lille, Lille, France.
authors: Julien
authors: J
authors: Labreuche
authors: 5 Department of Biostatistics, Lille University, CHU Lille, Lille, France.
authors: Francis
authors: F
authors: Vasseur
authors: 5 Department of Biostatistics, Lille University, CHU Lille, Lille, France.
authors: Alain
authors: A
authors: Duhamel
authors: 1 Department of Movement Disorders and Neurology, Lille University, CHU Lille, Lille, France 2 INSERM U1171, Lille University, Lille, France.
authors: Arnaud
authors: A
authors: Delval
authors: 3 Department of Molecular Biology and Pathology Centre, Lille University, CHU Lille, Lille, France.
authors: Thomas
authors: T
authors: Bardyn
authors: 2 INSERM U1171, Lille University, Lille, France.
authors: Jean-Christophe
authors: JC
authors: Devedjian
authors: 3 Department of Molecular Biology and Pathology Centre, Lille University, CHU Lille, Lille, France.
authors: Nathalie
authors: N
authors: Rouaix
authors: 6 Department of Nuclear Medicine, Lille University, CHU Lille, Lille, France.
authors: Gregory
authors: G
authors: Petyt
authors: 7 Departments of Clinical Pharmacology and Neurosciences, CIC9302, University Hospital and Paul Sabatier University, Toulouse, France.
authors: Christine
authors: C
authors: Brefel-Courbon
authors: 7 Departments of Clinical Pharmacology and Neurosciences, CIC9302, University Hospital and Paul Sabatier University, Toulouse, France.
authors: Fabienne
authors: F
authors: Ory-Magne
authors: 8 Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR CNRS 5293 and CHU de Bordeaux, Bordeaux, France.
authors: Dominique
authors: D
authors: Guehl
authors: 9 Department of Neurology and Movement Disorders - APHM Timone University Hospital and Institut de Neurosciences de la Timone, AMU-CNRS UMR 7289, Marseille, France.
authors: Alexandre
authors: A
authors: Eusebio
authors: 10 Department of Psychiatry and Neurology, CHU Grenoble, Grenoble, France.
authors: Valérie
authors: V
authors: Fraix
authors: 11 Department of Movement Disorders and Neurology, Centre d'Investigation Clinique, INSERM CIC 0802, INSERM U1084, Laboratoire de Neurosciences Expérimentales et Cliniques, CHU de Poitiers, Poitiers, France.
authors: Pierre-Jean
authors: PJ
authors: Saulnier
authors: 12 Department of Movement Disorders and Neurology, CHU Strasbourg, Strasbourg, France.
authors: Ouhaid
authors: O
authors: Lagha-Boukbiza
authors: 13 Department of Movement Disorders and Neurology, CHU Clermont-Ferrand, Clermont-Ferrand, France.
authors: Frank
authors: F
authors: Durif
authors: 14 Department of Movement Disorders and Neurology, INSERM, CIC04, CHU Nantes, Nantes, France.
authors: Mirela
authors: M
authors: Faighel
authors: 15 Department of Movement Disorders and Neurology, CHU Nice, Nice, France.
authors: Caroline
authors: C
authors: Giordana
authors: 16 Department of Neurology, EA- 425 Université Rennes 1 et CHU Pontchaillou, CHU Rennes, Rennes, France.
authors: Sophie
authors: S
authors: Drapier
authors: 17 Department of Neurology and INSERM CIC-CRB 0204, Rouen University Hospital, CHU Rouen Rouen, France.
authors: David
authors: D
authors: Maltête
authors: 12 Department of Movement Disorders and Neurology, CHU Strasbourg, Strasbourg, France.
authors: Christine
authors: C
authors: Tranchant
authors: 11 Department of Movement Disorders and Neurology, Centre d'Investigation Clinique, INSERM CIC 0802, INSERM U1084, Laboratoire de Neurosciences Expérimentales et Cliniques, CHU de Poitiers, Poitiers, France.
authors: Jean-Luc
authors: JL
authors: Houeto
authors: 10 Department of Psychiatry and Neurology, CHU Grenoble, Grenoble, France.
authors: Bettina
authors: B
authors: Debû
authors: 9 Department of Neurology and Movement Disorders - APHM Timone University Hospital and Institut de Neurosciences de la Timone, AMU-CNRS UMR 7289, Marseille, France.
authors: Jean-Philippe
authors: JP
authors: Azulay
authors: 8 Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR CNRS 5293 and CHU de Bordeaux, Bordeaux, France.
authors: François
authors: F
authors: Tison
authors: 1 Department of Movement Disorders and Neurology, Lille University, CHU Lille, Lille, France 18 INSERM U837/6 Lille JPARC, France.
authors: Alain
authors: A
authors: Destée
authors: 6 Department of Nuclear Medicine, Lille University, CHU Lille, Lille, France.
authors: Marie
authors: M
authors: Vidailhet
authors: 7 Departments of Clinical Pharmacology and Neurosciences, CIC9302, University Hospital and Paul Sabatier University, Toulouse, France 19 INSERM NS-PARK National Network, France.
authors: Olivier
authors: O
authors: Rascol
authors: 1 Department of Movement Disorders and Neurology, Lille University, CHU Lille, Lille, France 2 INSERM U1171, Lille University, Lille, France.
authors: Kathy
authors: K
authors: Dujardin
authors: 1 Department of Movement Disorders and Neurology, Lille University, CHU Lille, Lille, France 2 INSERM U1171, Lille University, Lille, France.
authors: Luc
authors: L
authors: Defebvre
authors: 2 INSERM U1171, Lille University, Lille, France 18 INSERM U837/6 Lille JPARC, France.
authors: Régis
authors: R
authors: Bordet
authors: 3 Department of Molecular Biology and Pathology Centre, Lille University, CHU Lille, Lille, France.
authors: Bernard
authors: B
authors: Sablonnière
authors: 1 Department of Movement Disorders and Neurology, Lille University, CHU Lille, Lille, France 2 INSERM U1171, Lille University, Lille, France 20 Department of Medical Pharmacology, Lille University, CHU Lille, Lille, France david.devos@chru-lille.fr.
authors: David
authors: D
authors: Devos
mesh_terms: D000368:Aged; D002394:Catechol O-Methyltransferase; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D004311:Double-Blind Method; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; D007980:Levodopa; D002394:Catechol O-Methyltransferase; D004298:Dopamine
keywords: Parkinson’s disease; cognitive disorders; levodopa; methylphenidate; pharmacogenetics