A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample
Guindalini, Camila [UNIFESP]
Laranjeira, Ronaldo [UNIFESP]
Bubb, V. J.
Murray, R. M.
Castelo Filho, Adauto [UNIFESP]
Quinn, J. P.
Is part ofProceedings of the National Academy of Sciences of the United States of America
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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.
CitationProceedings of the National Academy of Sciences of the United States of America. Washington: Natl Acad Sciences, v. 103, n. 12, p. 4552-4557, 2006.
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