Methylation and expression quantitative trait locus rs6296 in the HTR1B gene is associated with susceptibility to opioid use disorder
Methylation and expression quantitative trait locus rs6296 in the HTR1B gene is associated with susceptibility to opioid use disorder
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DOI：
10.1007/s00213-022-06141-5
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发表时间：
2022-04
影响因子：
3.4
通讯作者：
Yunxiao Li;Ye Lu;Q. Xie;Xiaofeng Zeng;Rui Zhang;Weibo Dang;Yongsheng Zhu;Jianbo Zhang
中科院分区：
文献类型：
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作者：
Yunxiao Li;Ye Lu;Q. Xie;Xiaofeng Zeng;Rui Zhang;Weibo Dang;Yongsheng Zhu;Jianbo Zhang
5-羟色胺(5-羟色胺)与物质使用障碍的奖赏过程有关。表观遗传和转录机制有助于成瘾状态的发展。为了探讨5-羟色胺受体基因在阿片类药物使用障碍中的可能机制，我们首先在1731名参与者中确定了三个有代表性的5-羟色胺受体基因(HTR1B、HTR2A和HTR3B)的几个单核苷酸多态性(SNPs)与海洛因使用障碍易感性的关系。分析了这些基因之间的基因-基因互作。在确定了海洛因使用障碍的易感基因和SNP后，比较了111例健康对照组和120例海洛因使用障碍患者这些易感基因启动子区域的DNA甲基化情况。此外，还检查了易感性SNPs与CpG位点甲基化和基因启动子甲基化之间的关系。最后，对易感基因SNPs在相应基因表达中的作用进行了筛选。我们的结果表明HTR1B基因的rs6296与海洛因使用障碍的易感性有关。对HTR1B和HTR2A基因之间的基因-基因互作进行了鉴定。海洛因使用障碍患者HTR1B_07、HTR1B_26 CpG位点及HTR1B基因启动子区甲基化水平明显高于正常对照组。值得注意的是，rs6296以等位基因特异性的方式与血液中HTR1B基因启动子的甲基化以及额叶皮质和下丘脑中HTR1B基因的基因表达相关。SNP rs6296与阿片类药物使用障碍有关，其机制涉及DNA甲基化和HTR1B基因表达。
Serotonin (5-HT) is implicated in the reward processes underlying substance use disorder. Epigenetic and transcriptional mechanisms contribute to the development of addictive states. To examine the potential mechanisms of 5-HT receptor genes in opioid use disorder, we first determined the associations between several single-nucleotide polymorphism (SNPs) in three representative 5-HT receptor genes (HTR1B,HTR2A, andHTR3B) and susceptibility to heroin use disorder in 1731 participants. Gene–gene interactions among these genes were analyzed. After identifying the susceptibility genes and SNPs for heroin use disorder, DNA methylation in the promoter region of these susceptibility genes was compared between 111 healthy controls and 120 patients with heroin use disorder. In addition, associations between the susceptibility SNPs and methylation of the CpG sites and gene promoters with differential methylation between groups were examined. Finally, the function of the susceptibility SNPs in the expression of the corresponding genes was screened. Our results demonstrated that rs6296 in theHTR1Bgene was correlated with susceptibility to heroin use disorder. Gene–gene interactions between theHTR1BandHTR2Agenes were identified. The CpG sitesHTR1B_07 andHTR1B_26 and the promoter region of theHTR1Bgene were hypermethylated in patients with heroin use disorder compared with healthy controls. Notably, rs6296 correlated in an allele-specific manner with methylation in theHTR1Bgene promoter in the blood and gene expression of theHTR1Bgene in the frontal cortex and hypothalamus. SNP rs6296 was associated with opioid use disorder by involving mechanisms of DNA methylation and expression of theHTR1Bgene.