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

Research output: Contribution to journalArticle

C. Guindalini, M. Howard, K. Haddley, R. Laranjeira, D. Collier, N. Ammar, I. Craig, C. O'Gara, V. J. Bubb, T. Greenwood, J. Kelsoe, P. Asherson, R. M. Murray, A. Castelo, J. P. Quinn, H. Vallada, G. Breen

Original languageEnglish
Pages (from-to)4552 - 4557
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number12
DOIs
Publication statusPublished - 21 Mar 2006

King's Authors

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 Sao 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.

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