Dopamine transporter (SLC6A3) 5′ region haplotypes significantly affect transcriptional activity in vitro but are not associated with Parkinsonʼs disease

• Published in: Pharmacogenetics and genomics Vol. 15; no. 9; pp. 659 - 668
• Main Authors: Kelada, Samir N, Costa-Mallen, Paola, Checkoway, Harvey, Carlson, Christopher S, Weller, Terri-Smith, Swanson, Phillip D, Franklin, Gary M, Longstreth, W. T, Afsharinejad, Zahra, Costa, Lucio G
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins, Inc 01-09-2005; Lippincott Williams and Wilkins
• Subjects: 3' Untranslated Regions; 5' Untranslated Regions; Adult; Aged; Alleles; Animals; Base Sequence; Biological and medical sciences; Case-Control Studies; Cloning, Molecular; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins; Exons; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; General pharmacology; Genes, Reporter; Genotype; Haplotypes; Humans; In Vitro Techniques; Male; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Middle Aged; Models, Genetic; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Odds Ratio; Parkinson Disease - genetics; PC12 Cells; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Plasmids - metabolism; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Rats; Sex Factors; Transcription, Genetic; Transcription. Transcription factor. Splicing. Rna processing; Transfection; Nervous system diseases; Pharmacogenetics; Dopamine; Parkinson's disease; Transcription; Parkinson disease; In vitro; Cerebral disorder; dopamine transporter; Central nervous system disease; Degenerative disease; Haplotype; Extrapyramidal syndrome; Polymorphism
• ISSN: 1744-6872; 1744-6880
• DOI: 10.1097/01.fpc.0000170917.04275.d6

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 Parkinsonʼs 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.