title: 5' and 3' region variability in the dopamine transporter gene (SLC6A3), pesticide exposure and Parkinson's disease risk: a hypothesis-generating study.
abstract: The dopamine transporter gene (SLC6A3) is a candidate gene for Parkinson's disease (PD) on the basis of its critical role in dopaminergic neurotransmission. Previously, we identified 22 SNPs in the 5' region of SLC6A3, which segregate as eight haplotypes that differ in transcriptional activity when transfected in rat dopamine-producing cells. In the present work from a case-control study size of 293 cases and 395 controls, we employed a cladistic approach to examine gene-disease association. First, we found strong evidence of balancing selection in this region, as determined by a Tajima's D statistic of 2.97 (P<0.001). Second, we found that the eight haplotypes fit into two main clades and that diplotypes of these clades were marginally associated with PD. Then, after we classified cases and controls by the number of risk alleles, accounting for the well-known 3' region VNTR polymorphism, we found that having two or more risk alleles resulted in a modest but significant increase in PD risk [odds ratio=1.58; 95% confidence interval (CI): 1.03-2.40]. Finally, we detected a significant interaction between occupational pesticide exposure in men and the number of risk alleles. Among pesticide-exposed subjects, the odds ratio for having two or more risk alleles was 5.66 (95% CI: 1.73-18.53). Thus, allelic variants in SLC6A3, which affect gene expression, are associated with PD in this population and may interact with occupational pesticide exposure to increase PD risk.
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA. keladas@mail.nih.gov
authors.forename: Samir N P
authors.initials: SN
authors.lastname: Kelada
authors.forename: Harvey
authors.initials: H
authors.lastname: Checkoway
authors.forename: Sharon L R
authors.initials: SL
authors.lastname: Kardia
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
authors.forename: Paola
authors.initials: P
authors.lastname: Costa-Mallen
authors.forename: David L
authors.initials: DL
authors.lastname: Eaton
authors.forename: Jordan
authors.initials: J
authors.lastname: Firestone
authors.forename: Karen M
authors.initials: KM
authors.lastname: Powers
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Swanson
authors.forename: Gary M
authors.initials: GM
authors.lastname: Franklin
authors.forename: W T
authors.initials: WT
authors.lastname: Longstreth
authors.forename: Terri-Smith
authors.initials: TS
authors.lastname: Weller
authors.forename: Zahra
authors.initials: Z
authors.lastname: Afsharinejad
authors.forename: Lucio G
authors.initials: LG
authors.lastname: Costa
mesh_terms: D024509:3' Flanking Region / Q000235:genetics; D024506:5' Flanking Region / Q000235:genetics; D016022:Case-Control Studies; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D018598:Minisatellite Repeats; D016273:Occupational Exposure; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology; D010575:Pesticides / Q000633:toxicity*; D020641:Polymorphism, Single Nucleotide
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D010575:Pesticides; C493214:SLC6A3 protein, human