A Dopamine Transporter Gene Functional Variant Associated with Cocaine Abuse.
Authors: †Camila Guindalini BSc, †Mark Howard PhD, Ronaldo Laranjeira MD PhD, David Collier PhD, Nik Ammar MSc, Ian Craig PhD, Colin O’Gara MRCPsych, Tiffany Greenwood PhD, John Kelsoe MD, Phil Asherson MD PhD, Robin M. Murray DSc FRCPPsych, Adauto Castelo MD PhD4, John Quinn PhD, Homero Vallada MD PhD, and Gerome Breen PhD.
Background: The dopamine transporter (DAT) mediates the active re-uptake of dopamine from the synapse and is a principal regulator of dopaminergic neurotransmission. Due to the complex pattern of variation and linkage disequilibrium in the DAT gene a more detailed examination of the locus and the identification of robust functional variants is essential for investigation of the role of this gene in disorders related to dopaminergic dysfunction.
Objective: To characterize the influence of functional genetic variants in the dopamine transporter on cocaine abuse. Design: VNTRs polymorphisms were characterized and genotyped in a Brazilian two samples of current cocaine abusers from the metropolitan region of São Paulo (total n=695) and in a control sample of healthy individuals with no past history of drug abuse (total n=855). Functional effects of the variants on gene expression were analyzed using conventional and novel reporter gene constructs.Results: A positive genotypic association was found between a 30bp VNTR in intron 8 of the DAT gene and cocaine abuse in both samples (combined Odds Ratio=1.35 95%CI=1.10-1.67; p=0.0047). Haplotype analyses using other polymorphisms in and near the gene indicate that the Int8 VNTR is the variant responsible for the observed association. The functional analyses demonstrated that the risk allele (allele 3) mediates a differential and increased response (6 fold) to stimulus in reporter constructs in comparison with the other common and “protective” allele 2. (p<<0.001) Discussion: We have demonstrated a robust association between cocaine abuse and a functional VNTR allele in the dopamine transporter, suggesting that this gene may play a role in the aetiology of cocaine abuse. However, the genetic association will require replication in cocaine abuse and examination in other drug abuse phenotypes to clarify the role of this variant in addictive processes.