A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample.
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.
Guindalini
Camila
C
Medical Research Council Social Genetic and Developmental Psychiatry Research Centre, Division of Psychological Medicine, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom.
Howard
Mark
M
Haddley
Kate
K
Laranjeira
Ronaldo
R
Collier
David
D
Ammar
Nik
N
Craig
Ian
I
O'Gara
Colin
C
Bubb
Vivian J
VJ
Greenwood
Tiffany
T
Kelsoe
John
J
Asherson
Phil
P
Murray
Robin M
RM
Castelo
Adauto
A
Quinn
John P
JP
Vallada
Homero
H
Breen
Gerome
G
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001938:Brazil; D019970:Cocaine-Related Disorders / Q000235:genetics*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics*; D011110:Polymorphism, Genetic
D050483:Dopamine Plasma Membrane Transport Proteins; D005819:Genetic Markers; C493214:SLC6A3 protein, human