Single nucleotide polymorphisms (SNPs) rs2283265 and rs1076560 located within intron 5 and 6 of the dopamine receptor D2 gene (DRD2) independently alter the transcription process in exon 6 leading to two isoforms of DRD2, that is, D2 long and D2 short.1 The authors of the attenuation of disease progression with Azilect given once daily (ADAGIO) trial highlighted that SNP rs2283265 and rs1076560 in the DRD2 gene are significantly associated with early favorable peak response following selective mono amine oxidase inhibitor (MAOI‐B) rasagiline therapy.2
The 681 patients who participated in the ADAGIO trial were included in this post hoc analysis. Patients were given either rasagiline or placebo in the original study. The change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score was studied in the early phase, that is, weeks 12 and 24, and in the delayed phase, that is, weeks 24 and 36 postrasagiline therapy.2
SNP rs2283265 was associated with significantly improved motor UPDRS score at week 12 posttherapy (mean motor UPDRS drop of 1.01) after adjusting the placebo response. The mean improvement in total UPDRS score was 2.02 in SNP rs2283265. However, the magnitude of improvement of rs2283265 on mental UPDRS subsection was much smaller (mean change −0.22). Similar favorable changes of the total UPDRS score of 2.04 were observed with SNP rs1076560, although the mean improvement in motor and mental UPDRS scores were not cited in this article. In contrast, patients with either one or no C alleles clinically deteriorated (mean change in total UPDRS of +0.74, motor UPDRS of +0.81, and mental UPDRS +0.06) when assessed at week 12. However, neither SNP showed any statistically significant UPDRS score change in the delayed phase after week 36.
This study failed to show any statistically significant improvement in the activities of daily living in early PD despite the mean total UPDRS score reduction by around 2 points. Also the fact that in the delayed group the association was not confirmed might indicate that such a peak effect is only detectable in the very early phase of PD when motor disability is very mild. Moreover, because this is a post hoc analysis of the ADAGIO, it falls into the risk of having been unpowered to detect true differences. A larger study on an independent cohort and a better understanding of the exact mechanism of rasagiline on SNP rs2283265 and rs1076560 in DRD 2 genes is necessary before they are used in clinical practice.
This, however, is the most comprehensive pharmacogenetic study on antiparkinsonian medications to date, and it improves our understanding of the variable response to rasagiline. Preliminary studies already showed that variants of the solute carrier family 6 gene (SLC6A3) are genetic modifiers of the treatment response to l‐dopa and methylphenidate in Parkinson's disease (PD).3 This additional discovery of the rasagiline responsive dopamine receptor gene variant pushes us a step further toward a more precise and personalized therapy during early PD.2, 4
Author Roles
1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript: A. Writing of the first draft, B. Review and Critique.
S.B.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B
E.H.: 1B, 1C, 2B, 3B
K.L.N.: 3A, 3B
Disclosures
Ethical Compliance Statement: We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest: The authors report no sources of funding or conflicts of interest.
Financial Disclosures for the previous 12 months: The authors report no financial disclosures.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
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