Variations in OPRK1, which encodes the kappa-opioid receptor, are associated with the risk for alcohol dependence. Sequencing DNAs with higher and lower risk haplotypes revealed an insertion/deletion (indel) with a net addition of 830 bp located 1986 bp upstream of the translation start site (1389 bp upstream of the transcription start site). We demonstrated that the upstream region extending from -1647 to -10 bp or from -2312 to -10 bp (relative to the translation start site) could function as a promoter in transient transfection assays. We then determined that the presence of the indel reduced transcriptional activity by half. We used a PCR assay to genotype individuals in 219 multiplex alcohol-dependent families of European American descent for the presence or absence of this indel. Family-based association analyses detected significant evidence of association of this insertion with alcoholism; the longer allele (with the indel), which had lower expression, is associated with higher risk for alcoholism. This indel is, therefore, a functional regulatory variation likely to explain at least part of the association of OPRK1 with alcohol dependence.

译文

:编码RK-阿片受体的OPRK1的变异与酒精依赖的风险有关。具有较高和较低风险单倍型的DNA测序显示插入/缺失(插入缺失),在翻译起始位点上游1986 bp(转录起始位点上游1389 bp)处净增加了830 bp。我们证明上游区域从-1647延伸到-10 bp或从-2312延伸到-10 bp(相对于翻译起始位点)可以在瞬时转染测定中起启动子的作用。然后,我们确定indel的存在使转录活性降低了一半。我们使用PCR分析法对欧洲裔的219个多重酒精依赖家族的个体进行基因分型,以确定是否存在此indel。基于家庭的关联分析发现了明显的证据表明这种插入与酒精中毒有关;具有较低表达的较长等位基因(具有插入缺失)与酒精中毒的风险较高相关。因此,该插入缺失是功能性调节变异,可能至少解释了OPRK1与酒精依赖性的关联的至少一部分。

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