Network analysis of the genomic basis of the placebo effect.
Network analysis of the genomic basis of the placebo effect.
复制标题
安慰剂效应的基因组基础的网络分析。
DOI：
10.1172/jci.insight.93911
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发表时间：
2017
期刊：
影响因子：
8
通讯作者：
Loscalzo,Joseph
中科院分区：
文献类型：
--
作者：
Wang,Rui-Sheng;Hall,KathrynT;Giulianini,Franco;Passow,Dani;Kaptchuk,TedJ;Loscalzo,Joseph
安慰剂效应是一种现象，在这种现象中，患者接受了非活性治疗（例如，惰性药丸），其医疗状况显示出感知或实际的改善。临床试验中的安慰剂效应已经研究了很多年，特别是因为安慰剂治疗经常作为随机临床试验设计的对照组。最近的观察表明，安慰剂效应可能会受到基因的影响。这一观察结果导致了“安慰剂”一词的出现，它指的是一组与基因组相关的介质，它们影响个体对安慰剂治疗的反应。在本研究中，我们对placehome进行了网络分析，并使用种子连接器算法在综合人机交互组中确定了一个placehome模块。placehome模块显著富含神经递质信号通路和脑特异性蛋白质。我们使用女性基因组健康研究（WGHS）试验的大型队列验证了安慰剂模块，并证明安慰剂模块显著富含基因，其snp可以改变试验安慰剂组的结果。为了深入了解安慰剂在不同疾病和药物治疗中的作用，我们使用网络接近度量来检查安慰剂家园模块与不同疾病模块和药物靶标模块的接近程度。结果表明，相互作用组中安慰剂家园模块与疾病模块的网络接近程度与相应疾病的安慰剂效应强度显著相关。安慰剂家园模块与受某些药物影响的分子通路的接近表明存在安慰剂-药物相互作用。本研究有助于理解介导安慰剂反应的分子机制，并为在临床试验中最大限度地减少其影响以及开发有意参与安慰剂反应的治疗策略奠定了基础。
The placebo effect is a phenomenon in which patients who are given an inactive treatment (e.g., inert pill) show a perceived or actual improvement in a medical condition. Placebo effects in clinical trials have been investigated for many years especially because placebo treatments often serve as the control arm of randomized clinical trial designs. Recent observations suggest that placebo effects may be modified by genetics. This observation has given rise to the term “placebome,” which refers to a group of genome-related mediators that affect an individual’s response to placebo treatments. In this study, we conduct a network analysis of the placebome and identify a placebome module in the comprehensive human interactome using a seed-connector algorithm. The placebome module is significantly enriched with neurotransmitter signaling pathways and brain-specific proteins. We validate the placebome module using a large cohort of the Women’s Genome Health Study (WGHS) trial and demonstrate that the placebome module is significantly enriched with genes whose SNPs modify the outcome in the placebo arm of the trial. To gain insights into placebo effects in different diseases and drug treatments, we use a network proximity measure to examine the closeness of the placebome module to different disease modules and drug target modules. The results demonstrate that the network proximity of the placebome module to disease modules in the interactome significantly correlates with the strength of the placebo effect in the corresponding diseases. The proximity of the placebome module to molecular pathways affected by certain drug classes indicates the existence of placebo-drug interactions. This study is helpful for understanding the molecular mechanisms mediating the placebo response, and sets the stage for minimizing its effects in clinical trials and for developing therapeutic strategies that intentionally engage it.