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.
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.
Camila
C
Guindalini
Mark
M
Howard
Kate
K
Haddley
Ronaldo
R
Laranjeira
David
D
Collier
Nik
N
Ammar
Ian
I
Craig
Colin
C
O'Gara
Vivian J
VJ
Bubb
Tiffany
T
Greenwood
John
J
Kelsoe
Phil
P
Asherson
Robin M
RM
Murray
Adauto
A
Castelo
John P
JP
Quinn
Homero
H
Vallada
Gerome
G
Breen
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