A functional haplotype implicated in vulnerability to develop cocaine dependence is associated with reduced PDYN expression in human brain.
A functional haplotype implicated in vulnerability to develop cocaine dependence is associated with reduced PDYN expression in human brain.
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与可卡因依赖易感性相关的功能性单倍型与人脑中 PDYN 表达减少有关
DOI：
10.1038/npp.2008.187
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发表时间：
2009-04
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
作者：
动啡肽和kappa阿片受体在可卡因、海洛因和酒精的奖励特性中起着重要作用。我们检测了前啡肽基因（PDYN）多态性与可卡因依赖和可卡因/酒精共依赖的关系。我们对106名可卡因依赖、可卡因/酒精共依赖或对照的白种人和204名非裔美国人的6个snp进行了基因分型，分别位于启动子区、外显子4编码区和3 '非翻译区（UTR）。在白种人中，我们发现3'UTR snp （rs910080、rs910079和rs2235749）与可卡因依赖和可卡因/酒精共依赖有点显著相关。这些snp处于高度连锁不平衡状态，构成一个单倍型块。单倍型CCT与可卡因依赖、可卡因联合依赖和可卡因/酒精共依赖显著相关（FDR， q分别=0.04和0.03）。我们以SNP rs910079为报告基因，利用SNaPshot法研究了PDYN等位基因特异性基因在8个杂合人死后大脑中的表达。C等位基因（rs910079）的表达量较低，比值在0.48 ~ 0.78之间，表明PDYN的CCT单倍型在尾状核和伏隔核中均较低表达。对43个死后大脑中PDYN总表达的分析也显示，具有CCT单倍型风险的受试者的前肌啡肽mRNA水平显著降低。这项研究提供了证据，表明3'UTR PDYN单倍型与人类背侧和腹侧纹状体中PDYN基因mRNA的低表达有关，该基因与可卡因成瘾和/或可卡因/酒精共同依赖的易发性有关。
Dynorphin peptides and the kappa opioid receptor play important roles in the rewarding properties of cocaine, heroin and alcohol. We tested polymorphisms of the prodynorphin gene (PDYN) for association with cocaine dependence and cocaine/alcohol codependence. We genotyped six SNPs, located in the promoter region, exon 4 coding and 3′ untranslated region (UTR), in 106 Caucasians and 204 African Americans who were cocaine dependent, cocaine/alcohol codependent or controls. In Caucasians, we found point-wise significant associations of 3′UTR SNPs (rs910080, rs910079, and rs2235749) with cocaine dependence and cocaine/alcohol codependence. These SNPs are in high linkage disequilibrium, comprising a haplotype block. The haplotype CCT was significantly experiment-wise associated with cocaine dependence and with combined cocaine dependence and cocaine/alcohol codependence (FDR, q=0.04 and 0.03, respectively). We investigated allele-specific gene expression of PDYN, using SNP rs910079 as a reporter, in postmortem human brains from eight heterozygous subjects, using SNaPshot assay. There was significantly lower expression for C allele (rs910079), with ratios ranging from 0.48 to 0.78, indicating lower expression of the CCT haplotype of PDYN in both the caudate and nucleus accumbens. Analysis of total PDYN expression in 43 postmortem brains also showed significantly lower levels of preprodynorphin mRNA in subjects having the risk CCT haplotype. This study provides evidence that a 3′UTR PDYN haplotype, implicated in vulnerability to develop cocaine addiction and/or cocaine/alcohol codependence, is related to lower mRNA expression of the PDYN gene in human dorsal and ventral striatum.
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影响因子：
5.3
作者：
Bray, NJ;Buckland, PR;O'Donovan, MC
通讯作者：
O'Donovan, MC
影响因子：
1.7
作者：
DAUNAIS, JB;ROBERTS, DCS;MCGINTY, JF
通讯作者：
MCGINTY, JF
影响因子：
5.3
作者：
Huang, Weihua;Ma, Jennie Z.;Li, Ming D.
通讯作者：
Li, Ming D.
DOI：
10.1016/0169-328x(92)90178-e
发表时间：
1992-07-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
BRANCH, AD;UNTERWALD, EM;KREEK, MJ
通讯作者：
KREEK, MJ
影响因子：
56.9
作者：
Gabriel, SB;Schaffner, SF;Altshuler, D
通讯作者：
Altshuler, D