Human Molecular Genetics Advance Access originally published online on September 8, 2006
Human Molecular Genetics 2006 15(20):3055-3062; doi:10.1093/hmg/ddl247
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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
1 Department of Environmental and Occupational Health Sciences, 2 Department of Epidemiology and 3 Department of Neurology, University of Washington, Seattle, WA 98105, USA, 4 Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA, 5 Fred Hutchinson Cancer Research Center, Seattle, WA, USA and 6 Department of Human Anatomy, Pharmacology and Forensic Sciences, University of Parma Medical School, Parma, Italy
* To whom correspondence should be addressed at: National Human Genome Research Institute, National Institutes of Health, Building 50, Room 5310, 50 South Drive MSC 8004, Bethesda, MD 20892, USA. Tel: +1 3014022270; Fax: +1 3014809667; Email: keladas{at}mail.nih.gov
Received July 28, 2006; Revised August 28, 2006; Accepted September 5, 2006
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.
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