5' and 3' region variability in the dopamine transporter gene (SLC6A3), pesticide exposure and Parkinson's disease risk: a hypothesis-generating study.
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.
Kelada
Samir N P
SN
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA. keladas@mail.nih.gov
Checkoway
Harvey
H
Kardia
Sharon L R
SL
Carlson
Christopher S
CS
Costa-Mallen
Paola
P
Eaton
David L
DL
Firestone
Jordan
J
Powers
Karen M
KM
Swanson
Phillip D
PD
Franklin
Gary M
GM
Longstreth
W T
WT
Weller
Terri-Smith
TS
Afsharinejad
Zahra
Z
Costa
Lucio G
LG
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
D050483:Dopamine Plasma Membrane Transport Proteins; D010575:Pesticides; C493214:SLC6A3 protein, human