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Sequence Variants in SLC6A3, DRD2, and BDNF Genes and Time to Levodopa-Induced Dyskinesias in Parkinson’s Disease

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Abstract

Levodopa-induced dyskinesias (LID) present a common but elusive complication of levodopa therapy in Parkinson’s disease (PD). In order to identify genetic factors associated with LID, 352 (213 males) levodopa-treated Israeli PD patients were genotyped for 34 polymorphisms within three candidate genes affecting dopaminergic activity and synaptic plasticity: dopamine transporter gene (DAT1 or SLC6A3) [14 single nucleotide polymorphisms (SNPs) and 40-bp variable number tandem repeat (VNTR)], DRD2 [11 SNPs and dinucleotide CA short tandem repeat (STR)], and BDNF (7 SNPs). A comparison of patients with and without LID was performed by applying a time-oriented approach, with survival analyses evaluating LID development hazard rate over time [Cox proportional hazards and accelerated failure time (AFT) lognormal models]. Overall, 192 (54.5 %) participants developed LID, with a mean latency of 5.0 (±4.5) years. After adjusting for gender, age at PD onset, duration of symptoms prior to levodopa exposure, and multiple testing correction, one SNP in SLC6A3 (with 81 % genotyping success) was significantly associated with LID latency: the C allele of the rs393795 extended the time to LID onset, time ratio = 4.96 (95 % CI, 2.3–10.9; p = 4.1 × 10−5). This finding should be validated in larger, ethnically diverse PD populations, and the biological mechanism should be explored.

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Acknowledgments

Special appreciation is due to Ms. Julia Feiler and Prof. Gideon Rechavi’s research laboratories, at Sheba Cancer Research Center laboratories, for the use of their facilities and equipment and assistance with operating the Sequenom MassARRAY® System technology. This study was supported by the Bharier Medical Fund, in memory of Nat and Sophie Bharier, and by the Mariana and George Saia Foundation (Tel Aviv University).

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The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. The Parkinson Disease and Movement Disorders Clinic, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel Hashomer, 52621, Ramat Gan, Israel

    Natalie Kaplan, Oren S. Cohen, Rivka Inzelberg, Gilad Yahalom, Evgenia Kozlova & Sharon Hassin-Baer

  2. The Susanne-Levy Gertner Oncogenetics Unit, The Institute of Human Genetics, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

    Roni Milgrom, Yael Laitman & Eitan Friedman

  3. The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Natalie Kaplan, Oren S. Cohen, Rivka Inzelberg, Eitan Friedman & Sharon Hassin-Baer

  4. The School of Mathematical Sciences, Tel Aviv University, Tel Aviv, Israel

    Aya Vituri & Saharon Rosset

  5. The Sieratzki Chair of Neurology, Tel Aviv University, Tel Aviv, Israel

    Amos D. Korczyn

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  1. Natalie Kaplan
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  2. Aya Vituri
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  3. Amos D. Korczyn
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  4. Oren S. Cohen
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  12. Sharon Hassin-Baer
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Correspondence to Sharon Hassin-Baer.

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Kaplan, N., Vituri, A., Korczyn, A.D. et al. Sequence Variants in SLC6A3, DRD2, and BDNF Genes and Time to Levodopa-Induced Dyskinesias in Parkinson’s Disease. J Mol Neurosci 53, 183–188 (2014). https://doi.org/10.1007/s12031-014-0276-9

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  • DOI: https://doi.org/10.1007/s12031-014-0276-9

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