title: Dopamine transporter (SLC6A3) 5' region haplotypes significantly affect transcriptional activity in vitro but are not associated with Parkinson's disease.
abstract: The dopamine transporter (DAT) plays a critical role in dopaminergic neurotransmission and is also the major site of action for some drugs of abuse. The coding region of the DAT gene, SLC6A3, is well conserved, but non-coding regions are more variable, most notably a variable number of tandem repeats (VNTR) polymorphism in the 3' untranslated region, which has been studied in a number of dopamine-related neurological disorders, including Parkinson's disease (PD). We aimed to characterize variation in the 5' region of SLC6A3 because little is known about the extent of variation in this region and potential consequences of such variation on gene expression. We identified multiple single nucleotide polymorphisms (SNPs) covering approximately 5000 bp 5' of exon 1 through the start of exon 2 (+2106). These SNPs segregated as eight haplotypes, six of which were common. These haplotypes differed significantly in activity in a reporter gene activity assay. However, we did not observe associations between common SNPs or haplotypes and PD in a case-control study of 261 incident cases and 376 age- and gender-matched unrelated controls. By contrast, we did observe a modest association of the 3' VNTR 9-repeat allele with PD (odds ratio=1.45; 95% confidence interval=1.04-2.03). This association was limited to subjects 60 years of age and greater versus those less than 60 years of age. We conclude that although DAT 5' region SNPs haplotypes significantly alter in vitro transcriptional activity, they are not related to PD risk. In addition, our findings provide further evidence supporting an association of PD with the VNTR polymorphism.
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105, USA. skelada@u.washington.edu
authors.forename: Samir N
authors.initials: SN
authors.lastname: Kelada
authors.forename: Paola
authors.initials: P
authors.lastname: Costa-Mallen
authors.forename: Harvey
authors.initials: H
authors.lastname: Checkoway
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
authors.forename: Terri-Smith
authors.initials: TS
authors.lastname: Weller
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: Zahra
authors.initials: Z
authors.lastname: Afsharinejad
authors.forename: Lucio G
authors.initials: LG
authors.lastname: Costa
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D003001:Cloning, Molecular; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D016017:Odds Ratio; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics*; D010957:Plasmids / Q000378:metabolism; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D012737:Sex Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493214:SLC6A3 protein, human; C493216:Slc6a3 protein, rat; D004298:Dopamine