Article

Journal of Molecular Neuroscience

, Volume 53, Issue 2, pp 183-188

First online:

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

  • Natalie KaplanAffiliated withThe Parkinson Disease and Movement Disorders Clinic, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical CenterThe Sackler Faculty of Medicine, Tel Aviv University
  • , Aya VituriAffiliated withThe School of Mathematical Sciences, Tel Aviv University
  • , Amos D. KorczynAffiliated withThe Sieratzki Chair of Neurology, Tel Aviv University
  • , Oren S. CohenAffiliated withThe Parkinson Disease and Movement Disorders Clinic, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical CenterThe Sackler Faculty of Medicine, Tel Aviv University
  • , Rivka InzelbergAffiliated withThe Parkinson Disease and Movement Disorders Clinic, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical CenterThe Sackler Faculty of Medicine, Tel Aviv University
  • , Gilad YahalomAffiliated withThe Parkinson Disease and Movement Disorders Clinic, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center
  • , Evgenia KozlovaAffiliated withThe Parkinson Disease and Movement Disorders Clinic, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center
  • , Roni MilgromAffiliated withThe Susanne-Levy Gertner Oncogenetics Unit, The Institute of Human Genetics, Chaim Sheba Medical Center
  • , Yael LaitmanAffiliated withThe Susanne-Levy Gertner Oncogenetics Unit, The Institute of Human Genetics, Chaim Sheba Medical Center
    • , Eitan FriedmanAffiliated withThe Susanne-Levy Gertner Oncogenetics Unit, The Institute of Human Genetics, Chaim Sheba Medical CenterThe Sackler Faculty of Medicine, Tel Aviv University
    • , Saharon RossetAffiliated withThe School of Mathematical Sciences, Tel Aviv University
    • , Sharon Hassin-BaerAffiliated withThe Parkinson Disease and Movement Disorders Clinic, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical CenterThe Sackler Faculty of Medicine, Tel Aviv University Email author 

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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.

Keywords

Levodopa-induced dyskinesias (LID) Parkinson’s disease Single nucleotide polymorphism (SNP) Dopamine transporter gene (SLC6A3) DRD2 BDNF