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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample
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A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample

机译：多巴胺转运蛋白基因功能变异与可卡因滥用有关的巴西样品

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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 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 μM cocaine was added to the cell culture (≈40% reduction of the 3 allele expression versus the 2 allele). The 3 allele also demonstrated ≈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.
机译：多巴胺（DA）转运蛋白DAT1是可卡因在大脑中结合的主要靶标。我们检查了DAT1中功能基因变异对可卡因成瘾的影响。在可卡因依赖的滥用者（n = 699）和没有过去药物滥用史的对照中，对重复多态性，包括内含子8（Int8 VNTR）中具有两个常见等位基因的30 bp可变数目串联重复序列（VNTR）进行基因分型。 （n = 866）来自巴西圣保罗。观察到与Int8 VNTR的等位基因3和可卡因滥用呈正相关（等位基因比值比= 1.2，95％置信区间= 1.01-1.37，P = 0.036; 3/3纯合子比值比= 1.45，95％置信区间= 1.18- 1.78，P = 0.0008）。对人口分层进行了评估，并不影响结果。使用其他多态性的单倍型分析表明，Int8 VNTR负责观察到的关联。在报告基因结构中的功能分析表明，与“保护性”等位基因2相比，等位基因3介导了显着的（P <0.05）但表达降低了。当向细胞培养物中添加1和10μM可卡因时，这种差异增加（≈40 3个等位基因表达相对于2个等位基因减少的百分比）。 3个等位基因还显示出对2个等位基因的表达比KCI加福司高林激发反应高约3倍。我们展示了可卡因依赖性和SLC6A3中的VNTR等位基因之间的稳固联系，赋予了很小但可检测的效果，并且我们证明了该VNTR可能具有功能。这项研究表明，DAT1基因变异可能在可卡因依赖病因中起作用。

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