5′ and 3′ region variability in the dopamine transporter gene ( SLC6A3 ), pesticide exposure and Parkinson's disease risk: a hypothesis-generating study

Kelada, Samir N.; Checkoway, Harvey; Kardia, Sharon L.R.; Carlson, Christopher S.; Costa-Mallen, Paola; Eaton, David L.; Firestone, Jordan A.; Powers, Karen M.; Swanson, Phillip D.; Franklin, Gary M.; Longstreth, W. T.; Weller, Terri Smith; Afsharinejad, Zahra; Costa, Lucio G.

doi:10.1093/hmg/ddl247

Cited by 59 publications

(45 citation statements)

References 78 publications

(70 reference statements)

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“…Interactions of paraoxonase and dopamine transporter genes and pesticides and PD also await replication. 29,30 To date, only an interaction of CYP2D6 gene polymorphisms and pesticides on the risk of PD has been independently replicated. 31,32 Information regarding specific subtypes of pesticides (e.g., by indication for use or by chemical class) and their association with PD is limited.…”

Section: Resultsmentioning

confidence: 99%

α-Synuclein, pesticides, and Parkinson disease

et al. 2008

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Section: Resultsmentioning

confidence: 99%

α-Synuclein, pesticides, and Parkinson disease

et al. 2008

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“…There are no conclusive results yet for the effect of the DAT VNTR as a risk factor for Parkinson disease. However, Kelada et al identified a haplotype corresponding with the T-A-9R haplotype that had a tendency of being a risk factor instead of a protective factor for Parkinson disease, though this was not significant (36). It remains difficult to understand the exact mechanisms of DAT expression, genotype, and the role of DAT in pathology, but the differences in DAT genotype and expression between healthy subjects and those who have disease might offer explanation of the crucial changes that reflect the pathologic mechanisms in disease.…”

Section: Discussionmentioning

confidence: 98%

Striatal Dopamine Transporter Availability Associated with Polymorphisms in the Dopamine Transporter Gene SLC6A3

Giessen¹,

Win²,

Tanck³

et al. 2008

J Nucl Med

141

111

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Polymorphisms in the dopamine transporter (DAT) gene SLC6A3 are associated with human striatal DAT expression, but the exact effects on DAT expression are not clear. A variable number of tandem repeats (VNTR) in the 39 untranslated region of the DAT gene was previously investigated in relation to striatal DAT availability, but the results were inconclusive. Other polymorphisms in the DAT gene were not extensively studied. Therefore, we investigated whether polymorphisms in both 39 and 59 ends of the DAT gene show association with in vivo striatal DAT expression. Methods: The subjects were an ethnically homogeneous group of 79 healthy young adults. Striatal DAT availability was measured with 123 I-(2-b-carbomethoxy-3-b(4-iodophenyl)-tropane) ( 123 I-b-CIT) SPECT. The 40-base-pair VNTR in the 39 untranslated region of the DAT gene and the 2 single nucleotide polymorphisms (SNPs) rs2652511 and rs2937639 in the 59 end of the DAT gene were genotyped. Multiple-regression analysis was performed for each of the 3 polymorphisms. Analysis of the combination of the polymorphisms (haplotype analysis) was conducted for the triad rs2652511-rs2937639-VNTR. Results: For the VNTR, the 9-repeat (9R) allele was associated with significantly higher striatal DAT expression than was the 10-repeat (10R) allele (P 5 0.002). Subanalysis suggested a dominant effect for the 9R allele. Neither SNP rs2652511 nor SNP rs2937639 was associated with striatal DAT availability. The haplotype T-A-9R (rs2652511-rs2937639-VNTR) was significantly more associated with higher striatal DAT expression than were the other haplotypes (P 5 0.009). Conclusion: The DAT VNTR 9R carriers have higher striatal DAT availability than do 10R homozygotes. This finding replicates former studies that included healthy subjects and also used 123 I-b-CIT SPECT. Our haplotype analysis identified a subgroup of 9R carriers, the T-A-9R, which appears to be mainly responsible for the association with higher striatal DAT availability. Thus, a combination of polymorphisms in both the 39 and the 59 ends of the DAT gene is associated with in vivo striatal DAT expression. This finding in healthy subjects may contribute to research on DAT availability and genotype in neuropsychiatric disorders.

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“…It is also shown to interact with its transcription factor NR4A2 in conferring risk for smoking (322). In addition, epigenetic and environmental involvement further complicates statistical evaluation of genetic associations with ADHD and Parkinson’s disease (298, 323, 324). …”

Section: The Transporter Genes As Risk Factorsmentioning

confidence: 99%

Monoamine Transporters

Lin¹,

Canales²,

Björgvinsson³

et al. 2011

Progress in Molecular Biology and Translational Science

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Transporters of dopamine, serotonin and norepinephrine have been empirically used as medication targets for several mental illnesses for the last decades. These protein-targeted medications are effective only for subpopulations of patients with transporter-related brain disorders. Since the cDNA clonings in early 1990’s, molecular studies of these transporters have revealed a wealth of information about the transporters’ structure activity relationship (SAR), neuropharmacology, cell biology, biochemistry, pharmacogenetics and the diseases related to the human genes encoding these transporters among related regulators. Such new information creates a unique opportunity to develop transporter-specific medications based on SAR, mRNA, DNA and perhaps transporter trafficking regulation, for a list of highly relevant diseases including substance abuse, depression, schizophrenia and Parkinson’s disease.

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5′ and 3′ region variability in the dopamine transporter gene ( SLC6A3 ), pesticide exposure and Parkinson's disease risk: a hypothesis-generating study

Cited by 59 publications

References 78 publications

α-Synuclein, pesticides, and Parkinson disease

α-Synuclein, pesticides, and Parkinson disease

Striatal Dopamine Transporter Availability Associated with Polymorphisms in the Dopamine Transporter Gene SLC6A3

Monoamine Transporters

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