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

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

Autor Guindalini, Camila Autor UNIFESP Google Scholar
Howard, M. Google Scholar
Haddley, K. Google Scholar
Laranjeira, Ronaldo Autor UNIFESP Google Scholar
Collier, D. Google Scholar
Ammar, N. Google Scholar
Craig, I Google Scholar
O'Gara, C. Google Scholar
Bubb, V. J. Google Scholar
Greenwood, T. Google Scholar
Kelsoe, J. Google Scholar
Asherson, P. Google Scholar
Murray, R. M. Google Scholar
Castelo Filho, Adauto Autor UNIFESP Google Scholar
Quinn, J. P. Google Scholar
Vallada, H. Google Scholar
Breen, G. Google Scholar
Instituição Kings Coll London
Universidade de São Paulo (USP)
Univ Liverpool
Universidade Federal de São Paulo (UNIFESP)
Univ Calif San Diego
San Diego Vet Affairs Healthcare Syst
Resumo 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.
Palavra-chave addiction
genetics
SLC6A3
Idioma Inglês
Data de publicação 2006-03-21
Publicado em Proceedings of the National Academy of Sciences of the United States of America. Washington: Natl Acad Sciences, v. 103, n. 12, p. 4552-4557, 2006.
ISSN 0027-8424 (Sherpa/Romeo, fator de impacto)
Publicador Natl Acad Sciences
Extensão 4552-4557
Fonte http://dx.doi.org/10.1073/pnas.0504789103
Direito de acesso Acesso aberto Open Access
Tipo Artigo
Web of Science WOS:000236362600042
Endereço permanente http://repositorio.unifesp.br/handle/11600/28794

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