TY - JOUR
T1 - A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample
AU - Guindalini, C.
AU - Howard, M.
AU - Haddley, K.
AU - Laranjeira, R.
AU - Collier, D.
AU - Ammar, N.
AU - Craig, I.
AU - O'Gara, C.
AU - Bubb, V. J.
AU - Greenwood, T.
AU - Kelsoe, J.
AU - Asherson, P.
AU - Murray, R. M.
AU - Castelo, A.
AU - Quinn, J. P.
AU - Vallada, H.
AU - Breen, G.
PY - 2006/3/21
Y1 - 2006/3/21
N2 - 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.
AB - 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.
U2 - 10.1073/pnas.0504789103
DO - 10.1073/pnas.0504789103
M3 - Article
SN - 1091-6490
VL - 103
SP - 4552
EP - 4557
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 12
ER -
