Elsevier

Parkinsonism & Related Disorders

Volume 47, February 2018, Pages 39-44
Parkinsonism & Related Disorders

Dopamine receptors and BDNF-haplotypes predict dyskinesia in Parkinson's disease

https://doi.org/10.1016/j.parkreldis.2017.11.339Get rights and content

Highlights

  • DRD genes (DRD1-3) and BDNF have been proposed to be involved in the development of dyskinesia.

  • DRD2 haplotypes, and potentially DRD3 haplotypes and rs6265 BDNF-SNP, were associated with dyskinesia.

  • Patients with these genetic markers appear prime candidate for testing approaches to prevent or delay dyskinesia development.

Abstract

Objective

Dyskinesia is a known side-effect of the treatment of Parkinson's Disease (PD). We examined the influence of haplotypes in three dopamine receptors (DRD1, DRD2 and DRD3) and the Brain Derived Neurotrophic Factor (BDNF) on dyskinesia.

Methods

Patient data were drawn from a population-based case-control study. We included 418 patients with confirmed diagnoses by movement disorder specialists, using levodopa and a minimum three years disease duration at the time of assessment. Applying Haploview and Phase, we created haploblocks for DRD1-3 and BDNF. Risk scores for DRD2 and DRD3 were generated. We calculated risk ratios using Poisson regression with robust error variance.

Results

There was no difference in dyskinesia prevalence among carriers of various haplotypes in DRD1. However, one haplotype in each DRD2 haploblocks was associated with a 29 to 50% increase in dyskinesia risk. For each unit increase in risk score, we observed a 16% increase in dyskinesia risk for DRD2 (95%CI: 1.05–1.29) and a 17% (95%CI: 0.99–1.40) increase for DRD3. The BDNF haploblock was not associated, but the minor allele of the rs6265 SNP was associated with dyskinesia (adjusted RR 1.31 (95%CI: 1.01–1.70)).

Conclusion

Carriers of DRD2 risk haplotypes and possibly the BDNF variants rs6265 and DRD3 haplotypes, were at increased risk of dyskinesia, suggesting that these genes may be involved in dyskinesia related pathomechanisms. PD patients with these genetic variants might be prime candidates for treatments aiming to prevent or delay the onset of dyskinesia.

Introduction

Parkinson's disease (PD) leads to significant disability and loss of quality-of-life [1]. One important component to loss of quality-of-life is l-dopa-induced dyskinesia, a common side-effect of treatment. Dyskinesia affects 25% within the first five years [2] increasing up to 80% among patients ten years into disease [3]. Dyskinesia is associated with depression and increases health-related costs [4]. Interestingly, although some patients develop dyskinesia early in their disease, other patients never do.

The two basal ganglia circuitry pathways (D1 and D2) associated with movement control are regulated by dopamine receptors. Common genetic variations in DRD loci are natural candidates for dyskinesia risk [5], [6]. In addition, Brain Derived Neurotrophic Factor (BDNF) may affect dyskinesia due to modulation of dopamine receptor expression [7], [8].

The majority of studies focused on DRD1-3 and BDNF. Many of these have concentrated on SNPs only, specifically the rs1800497 in DRD2 [9], [10], [11], [12], [13], [14], [15], [16], [17], the rs6280 in DRD3, [11], [13], [18] and the rs6265 in BDNF [9], [19], [20]. The results from these studies have reported inconsistent results [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. One small clinic-based study using a Brazilian population, analyzed DRD2 haplotypes (based on rs228365, rs1076560, rs6277, rs1800497 and rs2734849) and implicated that DRD2 haplotypes are associated with dyskinesia [14].

Here we are using a targeted approach for the three dopamine receptors (DRD1-3) and BDNF, to estimate risk of dyskinesia based on haplotypes' variants. Reviewing haplotypes instead of SNPs limits the number of tests and allows us to examine gene regions. Patients were enrolled in our large population-based study in California (N = 747) and dyskinesia was assessed relatively early, on average five years after first diagnosis based on cardinal motor symptoms.

Section snippets

Study population

We assembled a cohort from the population-based case control study Parkinson's Environment and Gene (PEG) study, which enrolled and followed patients from three Central California counties (Kern, Fresno, and Tulare) between 2001 and 2015. All patients were seen by movement disorder neurologists (JB, Dr. Bordelon) at least once at baseline, many on multiple follow-up occasions, and were confirmed as having probable idiopathic PD according to published criteria [21]. Recruitment occurred in two

Patient characteristics

The prevalence of dyskinesia in our patient sample was 24.6%, with the majority experiencing symptoms of dyskinesia less than 25% of their waking hours per day. The average age at diagnosis was 67 years, and on average 5.5 calendar years had passed since first diagnosis when we assessed dyskinesia in our study (see Table 1). Haplotype frequencies ranged between 4 and 51% in our haploblocks (supplemental figure e-2). The BDNF haplotype had a minimum frequency of 18.9% and a maximum of 45.4%.

Discussion

In our large community-based study of PD conducted in central California, we estimated an increased odds for developing dyskinesia after dopaminergic treatment in specific DRD2, DRD3, and BDNF but not DRD1 haplotype carriers. Our study finds that genetic variation in DRD2 influences the prevalence of dyskinesia and its severity in a dose response manner. Some variations in DRD3 and BDNF may further contribute to the risk and “severity of dyskinesia”. Our findings proved robust in sensitivity

Conclusion

Several haplotypes in DRD2, possibly haplotypes in DRD3 and the minor allele of rs6265 in BDNF, increased the risk of dyskinesia in our study. Levodopa induced dyskinesia and PD symptoms must be approached as a tradeoff. Nevertheless, genetic information may help prevent or postpone this debilitating consequence of treatment and may improve patient-centered, personalized therapy. Association studies require confirmation and the health care economy of implementing more personalized treatment

Author contributions

Jeff M Bronstein has evaluated the majority of patients to evaluate their Parkinson's disease status and symptoms; Ilaria Guella and Matt J Farrer were responsible for the genetic analysis and quality control; Matt J Farrer and Beate R Ritz were responsible for the conception, and overseeing the organization and execution; and the analysis were primarily performed by Cynthia DJ Kusters with the help of Kimberly C Paul, Janet S Sinsheimer and Beate R Ritz. The first draft of the article was

Conflicts of interest

None.

Funding sources

This project has been made available with funding from National Institutes of Health (grants: R01-ES010544, U54-ES012078, P01-ES016732, and P50-NS038367; initial pilot funding (P30-ES07048); NIH Training Grant in Genomic Analysis and Interpretation (T32HG002536)); Burroughs Wellcome Fund fellowships; a Community Fast Track grant by the MJFox Foundation; a pilot grant by the American Parkinson Disease Association; and Canada Excellence Research Chairs program. Leading Edge Endowment Funds

Acknowledgements

We would like to acknowledge the work performed by Stephanie F Bortnick (UBC) for the genotyping; Tara Candido for overseeing and managing the combined effort of UBC with UCLA; and Prof. Yvette Bordelon for her work as a movement specialist assessing the patients in this study. In addition, we would like to thank all the participants in this study.

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