Chen Andrew C H, LaForge K Steven, Ho Ann, McHugh Pauline F, Kellogg Scott, Bell Kathy, Schluger Rosemary P, Leal Suzanne M, Kreek Mary Jeanne
Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York 10021-6399, USA.
Am J Med Genet. 2002 May 8;114(4):429-35. doi: 10.1002/ajmg.10362.
It has been demonstrated that the opioid peptide dynorphin plays a role in modulating responses to several psychoactive substances including cocaine. Our laboratory and others have found that mRNA levels of dynorphin in the caudate and putamen are elevated after acute or chronic cocaine exposure in rats. Recently, a 68-base pair (bp) repeat polymorphism within the core promoter region of the human prodynorphin gene has been reported to occur in alleles containing one, two, three, or four copies. This repeat contains a putative AP-1 transcription factor binding site; reporter gene constructs with three or four, but not one or two, copies of the tandem repeats were shown to be associated with increases in transcriptional activation in in vitro cellular assays. We hypothesize that this polymorphism may be associated with individual differences in vulnerability to cocaine dependence or abuse. From an ongoing study of the genetics of addiction, 174 subjects were studied, including individuals with a primary diagnosis (DSM-IV criteria) of cocaine dependence (N = 61) or abuse (N = 22), and controls with no history of any substance dependence or abuse (N = 91). We designed primers for polymerase chain reaction (PCR) to amplify sequences of the promoter region of the prodynorphin gene containing the repeat element. The association of alleles containing three or four repeats with cocaine dependence/abuse was examined. With data stratified by ethnic group, pooled relative risk (RR) with Mantel-Haenszel Chi square was calculated: RR = 0.59 (95% confidence interval 0.37-0.95), chi2 (1) = 4.14, P = 0.042. Our results suggest that this allelic variation at the promoter region of the prodynorphin gene (alleles with three or four repeats), which may result in enhanced transcription of the gene, may contribute to relative protection and decrease individual vulnerability to develop cocaine dependence or abuse.
已有研究表明，阿片肽强啡肽在调节对包括可卡因在内的多种精神活性物质的反应中发挥作用。我们实验室及其他研究机构发现，大鼠急性或慢性接触可卡因后，其尾状核和壳核中强啡肽的mRNA水平会升高。最近，据报道人类前强啡肽基因核心启动子区域存在一个68个碱基对（bp）的重复多态性，该多态性存在于含有一、二、三或四个拷贝的等位基因中。这个重复序列包含一个假定的AP-1转录因子结合位点；在体外细胞试验中，含有三个或四个而非一或两个串联重复拷贝的报告基因构建体显示与转录激活增加有关。我们推测这种多态性可能与个体对可卡因依赖或滥用的易感性差异有关。在一项正在进行的成瘾遗传学研究中，对174名受试者进行了研究，包括初步诊断（符合DSM-IV标准）为可卡因依赖（N = 61）或滥用（N = 22）的个体，以及无任何物质依赖或滥用史的对照组（N = 91）。我们设计了用于聚合酶链反应（PCR）的引物，以扩增包含重复元件的前强啡肽基因启动子区域的序列。研究了含有三个或四个重复的等位基因与可卡因依赖/滥用之间的关联。根据种族分组对数据进行分层，计算合并相对风险（RR）及Mantel-Haenszel卡方检验：RR = 0.59（95%置信区间0.37 - 0.95），卡方值（1）= 4.14，P = 0.042。我们的结果表明，前强啡肽基因启动子区域的这种等位基因变异（含有三个或四个重复的等位基因）可能导致该基因转录增强，可能有助于相对保护作用并降低个体发生可卡因依赖或滥用的易感性。
