Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs
Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs
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DOI：
10.1038/s41380-018-0345-5
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发表时间：
2019-04-01
影响因子：
11
通讯作者：
White, F. A.
中科院分区：
文献类型：
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作者：
Niculescu, A. B.;Le-Niculescu, H.;White, F. A.
我们希望通过逐步发现、优先排序、验证和独立队列设计的测试来确定疼痛的客观血液生物标志物，疼痛是一种具有生物学基础的主观感觉。我们研究了精神病患者，这是一个患有共病疼痛障碍和疼痛感知增加的高危人群。对于发现，我们使用了强大的受试者内纵向设计。我们成功地确定了血液基因表达生物标志物，这些生物标志物可预测疼痛状态，以及未来急诊科（艾德）的疼痛就诊，尤其是当按性别和诊断进行个性化时。MFAP 3在文献中没有参与疼痛的先前证据，从我们的发现和验证步骤中获得了最有力的经验证据，并且是独立队列中疼痛的强有力预测因子，特别是在患有PTSD的女性和男性中。具有参与疼痛的最佳总体会聚功能证据的其他生物标志物是GNG 7、CNTN 1、LY 9、CCDC 144 B和GBP 1。一些已鉴定的生物标志物是现有药物的靶点。此外，生物标志物基因表达特征被用于生物信息学药物再利用分析，为可能的新药候选物提供线索，如SC-560（一种NSAID）和阿莫西林（一种抗抑郁药），以及天然化合物，如吡哆醇（维生素B6），氰钴胺（维生素B12）和芹菜素（一种植物类黄酮）。我们的工作可能有助于缓解导致当前阿片类药物流行的诊断和治疗困境。
We endeavored to identify objective blood biomarkers for pain, a subjective sensation with a biological basis, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We studied psychiatric patients, a high risk group for co-morbid pain disorders and increased perception of pain. For discovery, we used a powerful within-subject longitudinal design. We were successful in identifying blood gene expression biomarkers that were predictive of pain state, and of future emergency department (ED) visits for pain, more so when personalized by gender and diagnosis. MFAP3, which had no prior evidence in the literature for involvement in pain, had the most robust empirical evidence from our discovery and validation steps, and was a strong predictor for pain in the independent cohorts, particularly in females and males with PTSD. Other biomarkers with best overall convergent functional evidence for involvement in pain were GNG7, CNTN1, LY9, CCDC144B, and GBP1. Some of the individual biomarkers identified are targets of existing drugs. Moreover, the biomarker gene expression signatures were used for bioinformatic drug repurposing analyses, yielding leads for possible new drug candidates such as SC-560 (an NSAID), and amoxapine (an antidepressant), as well as natural compounds such as pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), and apigenin (a plant flavonoid). Our work may help mitigate the diagnostic and treatment dilemmas that have contributed to the current opioid epidemic.