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.

Classification of advanced stages of Parkinson’s disease: translation into stratified treatments

“…In a first study, DNA samples from 692 participants of the ADAGIO study that represented the largest clinical trial of early stage PD patients under monotherapy with rasagiline were genetically stratified for 197 genetic polymorphisms from 20 candidate genes (Masellis et al 2016). The candidate genes were chosen by their involvement in rasagiline’s mode of action or metabolism or based on previously reported genetic association with PD in genome-wide association studies (GWAS).…”

“…The candidate genes were chosen by their involvement in rasagiline’s mode of action or metabolism or based on previously reported genetic association with PD in genome-wide association studies (GWAS). The authors found a polymorphism in the dopamine D2 receptor gene as predictive for a meaningful clinical response to rasagiline treatment (Masellis et al 2016). This effect was not associated with the rate of symptom progression during the trial period.…”

Personalized medicine in Parkinson's disease: Time to be precise

“…In addition, single nucleotide polymorphisms rs2283265 and rs1076560 of the DRD2 gene have been reported to be significantly associated with a good response to rasagiline in early PD . Possible clinical implications are outlined in Table ; however, it must be pointed out that there are contradicting studies, and at this moment no definitive recommendations can be provided .…”

Genetic Variation and Neuroplasticity: Role in Rehabilitation After Stroke

“…53 While research is still in its early stages, recent work suggests that the presence of polymorphisms in the dopamine system in individuals with Parkinson disease may impact working memory and executive function 54–56 and be related to changes in brain activation in cortico-striatal networks. 57–59 Additionally, genotype may impact the effectiveness of dopamine drug therapies on motor symptoms 60, 61 and motor sequence learning 62 in those with Parkinson disease. Continued research is needed to fully understand the interaction between disease severity, drug therapies, motor behavior, and genotype in this clinical population and whether these interactions impact response to rehabilitation interventions.…”