Rights statement: This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Brain following peer review. The definitive publisher-authenticated version Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson’s disease: a pharmacogenetic study Mario Masellis, Shannon Collinson, Natalie Freeman, Maria Tampakeras, Joseph Levy, Amir Tchelet, Eli Eyal, Elijahu Berkovich, Rom E. Eliaz, Victor Abler, Iris Grossman, Cheryl Fitzer-Attas, Arun Tiwari, Michael R. Hayden, James L. Kennedy, Anthony E. Lang, Jo Knight, on behalf of the ADAGIO investigators Brain Jul 2016, 139 (7) 2050-2062; DOI: 10.1093/brain/aww109
Accepted author manuscript, 1.16 MB, PDF document
Available under license: CC BY-NC: Creative Commons Attribution-NonCommercial 4.0 International License
Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
TY - JOUR
T1 - Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson's disease
T2 - a pharmacogenetic study
AU - Masellis, Mario
AU - Collinson, Shannon
AU - Freeman, Natalie
AU - Tampakeras, Maria
AU - Levy, Joseph
AU - Tchelet, Amir
AU - Eyal, Eli
AU - Berkovich, Elijahu
AU - Eliaz, Rom E.
AU - Abler, Victor
AU - Grossman, Iris
AU - Fitzer-Attas, Cheryl
AU - Tiwari, Arun
AU - Hayden, Michael R.
AU - Kennedy, James L.
AU - Lang, Anthony E.
AU - Knight, Jo
AU - ADAGIO investigators
N1 - This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Brain following peer review. The definitive publisher-authenticated version Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson’s disease: a pharmacogenetic study Mario Masellis, Shannon Collinson, Natalie Freeman, Maria Tampakeras, Joseph Levy, Amir Tchelet, Eli Eyal, Elijahu Berkovich, Rom E. Eliaz, Victor Abler, Iris Grossman, Cheryl Fitzer-Attas, Arun Tiwari, Michael R. Hayden, James L. Kennedy, Anthony E. Lang, Jo Knight, on behalf of the ADAGIO investigators Brain Jul 2016, 139 (7) 2050-2062; DOI: 10.1093/brain/aww109
PY - 2016/7
Y1 - 2016/7
N2 - 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.
AB - 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.
KW - Parkinson’s disease
KW - rasagiline response
KW - polymorphism
KW - UPDRS
KW - DRD2
U2 - 10.1093/brain/aww109
DO - 10.1093/brain/aww109
M3 - Journal article
C2 - 27190009
VL - 139
SP - 2050
EP - 2062
JO - Brain
JF - Brain
SN - 0006-8950
IS - 7
ER -