Kuo Hsiang-Wei, Shih Chia-Lung, Tsung Jieh-Hen, Liu Sheng-Wen, Chu Shih-Kai, Yang Hsin-Chou, Tsou Hsiao-Hui, Wang Zih-Hsiang, Chen Andrew C H, Liu Yu-Li
Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.
Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
PLoS One. 2017 Mar 30;12(3):e0174647. doi: 10.1371/journal.pone.0174647. eCollection 2017.
Heroin dependent patients have a high incidence of HIV infection. In contrast to the gene expression method, we developed a systemic correlation analysis method built upon the results of pharmacogenomics study in a methadone maintenance treatment (MMT) cohort consisting of 344 Taiwanese heroin dependent patients. We identified genetic variants and their encoding proteins that may be involved with HIV infection and MMT treatment outcome. Cadherin 2 (CDH2) genetic determinants were identified through the genome-wide pharmacogenomic study. We found significant correlations among HIV infection status, plasma levels of CDH2, cytokine IL-7, ADAM10, and the treatment responses to methadone. Two single nucleotide polymorphisms located within CDH2 gene showed associations with blood pressure and plasma CDH2 concentration. Plasma concentration of CDH2 showed correlations with the level of cytokine IL-7, status of HIV infection, and urine morphine test result. Plasma level of IL-7 was correlated with corrected QT interval (QTc) and gooseflesh skin withdrawal symptom score, while level of ADAM10 was correlated with plasma concentrations of vitamin D metabolite, nicotine metabolite, and R-methadone. The results suggest a novel network involving HIV infection and methadone treatment outcome.
海洛因依赖患者的HIV感染发生率很高。与基因表达方法不同，我们基于对344名台湾海洛因依赖患者组成的美沙酮维持治疗（MMT）队列的药物基因组学研究结果，开发了一种系统相关性分析方法。我们鉴定出了可能与HIV感染和美沙酮治疗结果有关的基因变异及其编码蛋白。通过全基因组药物基因组学研究确定了钙黏蛋白2（CDH2）的遗传决定因素。我们发现HIV感染状态、CDH2血浆水平、细胞因子IL-7、ADAM10以及对美沙酮的治疗反应之间存在显著相关性。位于CDH2基因内的两个单核苷酸多态性与血压和血浆CDH2浓度有关。CDH2的血浆浓度与细胞因子IL-7水平、HIV感染状态和尿吗啡检测结果相关。IL-7的血浆水平与校正QT间期（QTc）和鸡皮样皮肤戒断症状评分相关，而ADAM10水平与维生素D代谢物、尼古丁代谢物和R-美沙酮的血浆浓度相关。结果提示了一个涉及HIV感染和美沙酮治疗结果的新网络。
