title: Sequence variants in SLC6A3, DRD2, and BDNF genes and time to levodopa-induced dyskinesias in Parkinson's disease.
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.
authors.affiliation: The Parkinson Disease and Movement Disorders Clinic, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel Hashomer, 52621, Ramat Gan, Israel.
authors.forename: Natalie
authors.initials: N
authors.lastname: Kaplan
authors.forename: Aya
authors.initials: A
authors.lastname: Vituri
authors.forename: Amos D
authors.initials: AD
authors.lastname: Korczyn
authors.forename: Oren S
authors.initials: OS
authors.lastname: Cohen
authors.forename: Rivka
authors.initials: R
authors.lastname: Inzelberg
authors.forename: Gilad
authors.initials: G
authors.lastname: Yahalom
authors.forename: Evgenia
authors.initials: E
authors.lastname: Kozlova
authors.forename: Roni
authors.initials: R
authors.lastname: Milgrom
authors.forename: Yael
authors.initials: Y
authors.lastname: Laitman
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.forename: Saharon
authors.initials: S
authors.lastname: Rosset
authors.forename: Sharon
authors.initials: S
authors.lastname: Hassin-Baer
mesh_terms: D000328:Adult; D000368:Aged; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D016022:Case-Control Studies; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D004409:Dyskinesia, Drug-Induced / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D010300:Parkinson Disease / Q000188:drug therapy; D020641:Polymorphism, Single Nucleotide; D017448:Receptors, Dopamine D2 / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C581293:DRD2 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; C493214:SLC6A3 protein, human; D007980:Levodopa; C579455:BDNF protein, human