A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample

Abstract

The dopamine (DA) transporter DAT1 is a major target bound by cocaine in brain. We examined the influence of functional genetic variants in DAT1 on cocaine addiction. Repeat polymorphisms, including a 30-bp variable-number tandem repeat (VNTR) in intron 8 (Int8 VNTR) with two common alleles, were genotyped in cocaine-dependent abusers (n ‫؍‬ 699) and in controls with no past history of drug abuse (n ‫؍‬ 866) from Sã o Paulo, Brazil. Positive association was observed with allele 3 of the Int8 VNTR and cocaine abuse (allele odds ratio ‫؍‬ 1.2, 95% confidence interval ‫؍‬ 1.01-1.37, P ‫؍‬ 0.036; 3͞3 homozygote odds ratio ‫؍‬ 1.45, 95% confidence interval ‫؍‬ 1.18 -1.78, P ‫؍‬ 0.0008). Population stratification was assessed and did not affect the results. Haplotypic analyses using additional polymorphisms indicated that the Int8 VNTR is responsible for the observed association. Functional analyses in reportergene constructs, demonstrated that allele 3 mediates significant (P < 0.05) but small reduced expression compared with the ''protective'' allele 2. This difference increased when 1 and 10 M cocaine was added to the cell culture (Ϸ40% reduction of the 3 allele expression versus the 2 allele). The 3 allele also demonstrated Ϸ3-fold-increased expression over the 2 allele in response to KCl plus forskolin challenge. We demonstrate a robust association between cocaine dependence and a VNTR allele in SLC6A3, conferring a small but detectible effect, and we show that this VNTR may be functional. This study suggests that DAT1 gene variation may play a role in cocaine dependence etiology.addiction ͉ genetics ͉ SLC6A3

Dopaminergic genotype biases spatial attention in healthy children

“…27,28 An additional VNTR within intron 8 has recently been identified and is associated with both cocaine abuse and ADHD. 22,29 A preliminary study using a reporter gene construct found evidence that this VNTR is functional, with the 3-repeat allele showing reduced expression and heightened sensitivity to cocaine, relative to a 2-repeat allele. 29 Nevertheless, a regulatory role of the intron 8 VNTR in normally expressing DAT1 cells is yet to be established.…”

“…22,29 A preliminary study using a reporter gene construct found evidence that this VNTR is functional, with the 3-repeat allele showing reduced expression and heightened sensitivity to cocaine, relative to a 2-repeat allele. 29 Nevertheless, a regulatory role of the intron 8 VNTR in normally expressing DAT1 cells is yet to be established. Linking variation in the intron 8 marker to individual differences in cognition is an important next step in helping to establish the functional candidacy of this marker.…”

Association analysis between a VNTR intron 8 polymorphism of the dopamine transporter gene (SLC6A3) and obsessive- compulsive disorder in a Brazilian sample

“…This polymorphism was studied in cocaine abuse and hyperactivity disorder (ADHD) patients showing a positive association with these disorders 19,24 . However, as far as we know, this is the fi rst association study analyzing this polymorphism in an OCD sample.…”

“…PCR products were separated on 2% agarose gels stained with ethidium bromide and viewed under UV light. The primers used were previously described in Guindalini et al 19 .…”

Addiction Research Centres and the Nurturing of Creativity. National Institute on Alcohol and Drugs Policies, Brazil

“…Our research group has conducted several major studies examining the genetic aspects of alcohol-and drugrelated disorders over the last few years [33][34][35][36][37][38][39]. This is an important area of research at our institute, and a project evaluating genetic vulnerabilities to cocaine addiction will be performed.…”