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

• Autor(a) principal: Guindalini, Camila [UNIFESP]
• Data de Publicação: 2006
• Outros Autores: Howard, M., Haddley, K., Laranjeira, Ronaldo [UNIFESP], Collier, D., Ammar, N., Craig, I, O'Gara, C., Bubb, V. J., Greenwood, T., Kelsoe, J., Asherson, P., Murray, R. M., Castelo Filho, Adauto [UNIFESP], Quinn, J. P., Vallada, H., Breen, G.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: http://repositorio.unifesp.br/handle/11600/28794; http://dx.doi.org/10.1073/pnas.0504789103
• topic: addiction; genetics; SLC6A3

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 São 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; 3/3 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 reporter-gene 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 mu M cocaine was added to the cell culture (approximate to 40% reduction of the 3 allele expression versus the 2 allele). the 3 allele also demonstrated approximate to 3-fold-increased expression over the 2 allele in response to KCI 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.