Student Research: Samir Kelada

PhD, , 2006
Faculty Advisor: Lucio G. Costa

5' and 3' Region Variability in the Dopamine Transporter Gene (SLC6A3) and Parkinson's Disease


Abstract

The dopamine transporter gene, SLC6A3, is a candidate gene for Parkinson's disease (PD) based on its critical role in dopamine neurotransmission, regulation by alpha-synuclein, and role as a gateway for neurotoxicants. The coding region of the gene 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. The first aim of this project was 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. Twenty-two SNPs were identified in the region spanning 5000 base pairs 5' of exon 1 through the start of exon 2 (+2106), which segregated into six common and two rare haplotypes, and more broadly into two major clades. The six common haplotypes differed significantly in transcriptional activity in a reporter gene assay. Subsequently, in the second aim of this project, both 5' and 3' polymorphisms were tested for association with PD. Modest associations between both 5' and 3' regions were detected, and, more importantly, stronger associations were detected when both regions where examined simultaneously. The relative risk estimates for being in the intermediate and high risk genotype 5'-3' categories were 1.16 (95% confidence interval: 0.75-1.78) and 1.58 (95% confidence interval: 1.03-2.40), respectively. Significant interactions between these genotypes and occupational pesticide exposure were also found. The results of this study suggest that both 5' and 3' regions of this gene affect risk of PD and that the gene may also modify the relationship between pesticide exposure and PD.