The kappa opioid receptor (KOR) plays a role in stress responsivity, opiate withdrawal and responses to cocaine. KOR activation by its endogenous ligand dynorphin A(1-17) decreases basal and drug-induced striatal levels of dopamine. The complete structure of the human KOR gene (hOPRK1) has not been previously determined. This study: (i) characterized the genomic structure of the hOPRK1 gene; (ii) identified single nucleotide polymorphisms (SNPs) in the hOPRK1 gene; and (iii) investigated possible associations of these variants with vulnerability to develop heroin addiction. Analysis of 5'-RACE cDNA clones revealed the presence of a novel exon 1 ranging in length from 167 to 251 nucleotides in the 5' 5'-untranslated region of the hOPRK1 mRNA. We found that the hOPRK1 gene has four major exons and three introns, similar to rodent OPRK1 genes. Direct sequencing of amplified DNA containing all four exons and intron 1 of the hOPRK1 gene were evaluated for polymorphisms in 291 subjects (145 former heroin addicts and 146 controls). Twelve SNPs were identified, nine novel variants and three previously reported SNPs. Using logistic regression with opioid dependence as the dependent variable, the 36G>T SNP exhibited a point-wise significant association (P = 0.016) with disease status. The number of haplotypes seen in the three ethnic groups were nine, six and five for African-Americans, Caucasians, and Hispanics, respectively, with corresponding significance levels for differences in haplotype frequencies between cases and controls of P = 0.0742, 0.1015 and 0.0041. Combining ethnicities by Fisher's method yields an empirical significance level of P = 0.0020.

译文

:κ阿片受体(KOR)在应激反应,阿片戒断和对可卡因的反应中起作用。 KOR激活通过其内源性配体强啡肽A(1-17)降低基础和药物引起的纹状体多巴胺水平。人KOR基因(hOPRK1)的完整结构以前尚未确定。这项研究:(i)鉴定了hOPRK1基因的基因组结构; (ii)在hOPRK1基因中鉴定出单核苷酸多态性(SNP); (iii)研究了这些变异与海洛因成瘾易感性之间的可能联系。 5'-RACE cDNA克隆的分析表明,在hOPRK1 mRNA的5'5'非翻译区中存在长度为167至251个核苷酸的新型外显子1。我们发现hOPRK1基因具有四个主要外显子和三个内含子,与啮齿动物OPRK1基因相似。在291名受试者(145名前海洛因成瘾者和146名对照)中,对包含hOPRK1基因的所有四个外显子和内含子1的扩增DNA的直接测序进行了多态性评估。鉴定出十二个SNP,九个新变体和三个先前报道的SNP。使用阿片类药物依赖性作为因变量的逻辑回归,36G> T SNP与疾病状况呈逐点显着相关性(P = 0.016)。在这三个族裔群体中,非裔美国人,白种人和西班牙裔分别看到的单倍型数量分别为九,六和五,对于病例与对照之间的单倍型频率差异,相应的显着性水平为P = 0.0742、0.1015和0.0041。通过费舍尔方法将种族组合在一起,得出的经验显着性水平为P = 0.0020。

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