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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 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 muM cocaine was added to the cell culture ( approximately 40% reduction of the 3 allele expression versus the 2 allele). The 3 allele also demonstrated approximately 3-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 detectable 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.
AuthorsCamila Guindalini, Mark Howard, Kate Haddley, Ronaldo Laranjeira, David Collier, Nik Ammar, Ian Craig, Colin O'Gara, Vivian J Bubb, Tiffany Greenwood, John Kelsoe, Phil Asherson, Robin M Murray, Adauto Castelo, John P Quinn, Homero Vallada, Gerome Breen
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 12 Pg. 4552-7 (Mar 21 2006) ISSN: 0027-8424 [Print] United States
PMID16537431 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Dopamine Plasma Membrane Transport Proteins
  • Genetic Markers
  • SLC6A3 protein, human
Topics
  • Adolescent
  • Adult
  • Alleles
  • Brazil
  • Cocaine-Related Disorders (genetics)
  • Dopamine Plasma Membrane Transport Proteins (genetics)
  • Female
  • Gene Frequency
  • Genetic Markers
  • Genotype
  • Haplotypes
  • Humans
  • Introns (genetics)
  • Male
  • Minisatellite Repeats (genetics)
  • Polymorphism, Genetic

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