Human Molecular Genetics Advance Access published online on September 8, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl247
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105; National Human Genome Research Institute, National Institutes of Health Building 50 Room 5310, 50 South Drive MSC 8004, Bethesda, MD 20892
* To whom correspondence should be addressed. The dopamine transporter gene (SLC6A3) is a candidate gene for Parkinson's disease (PD) based on 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 that affect gene expression are associated with PD in this population and may interact with occupational pesticide exposure to increase PD risk.
Received July 28, 2006
Revised August 28, 2006
Accepted September 5, 2006
Article
5' and 3' Region Variability in the Dopamine Transporter Gene (SLC6A3), Pesticide Exposure and Parkinson's Disease Risk: A Hypothesis Generating Study
Samir N.P. Kelada 1 *, Harvey Checkoway 2, Sharon L.R. Kardia 3, Christopher S. Carlson 4, Paola Costa-Mallen 5, David L. Eaton 5, Jordan Firestone 6, Karen M. Powers 5, Phillip D. Swanson 7, Gary M. Franklin 6, W. T. Longstreth Jr. 8, Terri-Smith Weller 5, Zahra Afsharinejad 5, and Lucio G. Costa 9
2 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105; Department of Epidemiology, University of Washington, Seattle, WA 98105
3 Department of Epidemiology, University of Michigan School of Public Health, Italy
4 Fred Hutchinson Cancer Research Center, Italy
5 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105
6 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105; Department of Neurology, University of Washington, Seattle, WA 98105
7 Department of Neurology, University of Washington, Seattle, WA 98105
8 Department of Epidemiology, University of Washington, Seattle, WA 98105; Department of Neurology, University of Washington, Seattle, WA 98105
9 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105; University of Parma Medical School, Italy
Samir N.P. Kelada, E-mail: keladas{at}mail.nih.gov
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Brighina, R. Frigerio, N. K. Schneider, T. G. Lesnick, M. de Andrade, J. M. Cunningham, M. J. Farrer, S. J. Lincoln, H. Checkoway, W. A. Rocca, et al. {alpha}-Synuclein, pesticides, and Parkinson disease: A case-control study Neurology, April 15, 2008; 70(16_Part_2): 1461 - 1469. [Abstract] [Full Text] [PDF]
|
|