title: Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson's disease: a pharmacogenetic study.
abstract: The treatment of early Parkinson's disease with dopaminergic agents remains the mainstay of symptomatic therapy for this incurable neurodegenerative disorder. However, clinical responses to dopaminergic drugs vary substantially from person to person due to individual-, drug- and disease-related factors that may in part be genetically determined. Using clinical data and DNA samples ascertained through the largest placebo-controlled clinical trial of the monoamine oxidase B inhibitor, rasagiline (ClinicalTrials.gov number, NCT00256204), we examined how polymorphisms in candidate genes associate with the clinical response to rasagiline in early Parkinson's disease. Variants in genes that express proteins involved in the pharmacokinetics and pharmacodynamics of rasagiline, and genes previously associated with the risk to develop Parkinson's disease were genotyped. The LifeTechnologies OpenArray NT genotyping platform and polymerase chain reaction-based methods were used to analyse 204 single nucleotide polymorphisms and five variable number tandem repeats from 30 candidate genes in 692 available DNA samples from this clinical trial. The peak symptomatic response to rasagiline, the rate of symptom progression, and their relation to genetic variation were examined controlling for placebo effects using general linear and mixed effects models, respectively. Single nucleotide polymorphisms, rs2283265 and rs1076560, in the dopamine D2 receptor gene (DRD2) were found to be significantly associated with a favourable peak response to rasagiline at 12 weeks in early Parkinson's disease after controlling for multiple testing. From a linear regression, the betas were 2.5 and 2.38, respectively, with false discovery rate-corrected P-values of 0.032. These polymorphisms were in high linkage disequilibrium with each other (r(2) = 0.96) meaning that the same clinical response signal was identified by each of them. No polymorphisms were associated with slowing the rate of worsening in Parkinson symptoms from Weeks 12 to 36 after correction for multiple testing. This is the largest and most comprehensive pharmacogenetics study to date examining clinical response to an anti-parkinsonian drug and the first to be conducted in patients with early stage Parkinson's disease receiving monotherapy. The results indicate a clinically meaningful benefit to rasagiline in terms of the magnitude of improvement in parkinsonian symptoms for those with the favourable response genotypes. Future work is needed to elucidate the specific mechanisms through which these DRD2 variants operate in modulating the function of the nigrostriatal dopaminergic system.media-1vid110.1093/brain/aww109_video_abstractaww109_video_abstract.
authors.affiliation: 1 Cognitive and Movement Disorders Clinic, Sunnybrook Health Sciences Centre, Toronto, Canada 2 Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Canada 3 Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada 4 Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada 5 Institute of Medical Science, University of Toronto, Toronto, Canada mario.masellis@sunnybrook.ca.
authors.forename: Mario
authors.initials: M
authors.lastname: Masellis
authors.affiliation: 4 Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada.
authors.forename: Shannon
authors.initials: S
authors.lastname: Collinson
authors.affiliation: 4 Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada.
authors.forename: Natalie
authors.initials: N
authors.lastname: Freeman
authors.affiliation: 4 Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Tampakeras
authors.affiliation: 6 Teva Pharmaceutical Industries, Israel.
authors.forename: Joseph
authors.initials: J
authors.lastname: Levy
authors.affiliation: 6 Teva Pharmaceutical Industries, Israel.
authors.forename: Amir
authors.initials: A
authors.lastname: Tchelet
authors.affiliation: 6 Teva Pharmaceutical Industries, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Eyal
authors.affiliation: 6 Teva Pharmaceutical Industries, Israel.
authors.forename: Elijahu
authors.initials: E
authors.lastname: Berkovich
authors.affiliation: 6 Teva Pharmaceutical Industries, Israel.
authors.forename: Rom E
authors.initials: RE
authors.lastname: Eliaz
authors.affiliation: 6 Teva Pharmaceutical Industries, Israel.
authors.forename: Victor
authors.initials: V
authors.lastname: Abler
authors.affiliation: 6 Teva Pharmaceutical Industries, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Grossman
authors.affiliation: 6 Teva Pharmaceutical Industries, Israel.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Fitzer-Attas
authors.affiliation: 4 Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada.
authors.forename: Arun
authors.initials: A
authors.lastname: Tiwari
authors.affiliation: 6 Teva Pharmaceutical Industries, Israel.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: 4 Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada 5 Institute of Medical Science, University of Toronto, Toronto, Canada 7 Department of Psychiatry, University of Toronto, Toronto, Canada 8 Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada.
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.affiliation: 3 Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada 9 Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, Canada 10 The Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University Health Network, Toronto, Canada.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Lang
authors.affiliation: 4 Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada 5 Institute of Medical Science, University of Toronto, Toronto, Canada 7 Department of Psychiatry, University of Toronto, Toronto, Canada 8 Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada 11 Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada 12 Lancaster Medical School and Data Science Institute, Lancaster University, Lancaster, UK.
authors.forename: Jo
authors.initials: J
authors.lastname: Knight
mesh_terms: D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D017063:Outcome Assessment, Health Care; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics*; D000071185:Pharmacogenomic Testing / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D012720:Severity of Illness Index; D020080:Tandem Repeat Sequences
chemical_list: C581293:DRD2 protein, human; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D017448:Receptors, Dopamine D2; C031967:rasagiline
keywords: DRD2; Parkinson’s disease; UPDRS; polymorphism; rasagiline response