Systems biology-based approaches to summarize and identify novel genes and pathways associated with acute and chronic postsurgical pain
Systems biology-based approaches to summarize and identify novel genes and pathways associated with acute and chronic postsurgical pain
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DOI：
10.1016/j.jclinane.2020.109738
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发表时间：
2020-06-01
影响因子：
6.7
通讯作者：
Jegga, Anil G.
中科院分区：
文献类型：
--
作者：
Chidambaran, Vidya;Ashton, Maria;Jegga, Anil G.
研究目的：采用基于系统生物学的机器学习来识别遗传变异过度表现的生物过程设计：基于信息系统生物学的综合计算分析。设置：儿科研究和教学机构。干预措施：进行Pubmed检索（01/01/2001-10/31/2017），以确定与人类术后疼痛相关的“训练”基因。候选基因进行了鉴定和优先使用Toppgene套件，基于功能富集使用几个基因本体论注释，并策划与小鼠表型敲除studies.Measurements相关的基因集：计算排名靠前的候选基因和文献策划的基因被包括在途径富集分析。层次聚类被用来可视化两个phenotype.Main结果之间的选择功能富集结果：文献综述确定了38训练基因与术后疼痛和31与CPSP。我们确定了2610个可能与急性和慢性术后疼痛相关的优先新型候选基因，前10百分位数共同富集了（p 0.05; Benjamini-Hochberg校正）几种途径，最重要的是cAMP反应元件结合蛋白和离子通道途径。热图显示丰富的炎症/药物代谢过程中的急性术后疼痛和免疫机制在CPSP.Conclusion：高个体间差异的疼痛反应后立即手术和风险CPSP建议遗传易感性。缺乏大的同质样本量导致了动力不足的遗传关联研究。系统生物学可以用来整合基因水平的数据与生物过程，以生成优先的候选基因列表，并了解涉及急性术后疼痛和CPSP的新生物学途径。这些数据将是为未来的多基因研究提供有针对性的全基因组分析的关键。这项研究证明了基于功能注释的优先化和富集方法的实用性，并鉴定了涉及急性和慢性术后疼痛的新基因和独特/共享的生物学过程。研究结果为未来CPSP风险的靶向遗传分析提供了框架，以实现预防和治疗方法。
Study objective: To employ systems biology-based machine learning to identify biologic processes over-represented with genetic variants (gene enrichment) implicated in post-surgical pain.Design: Informed systems biology based integrative computational analyses.Setting: Pediatric research and teaching institution.Interventions: Pubmed search (01/01/2001-10/31/2017) was performed to identify "training" genes associated with postoperative pain in humans. Candidate genes were identified and prioritized using Toppgene suite, based on functional enrichment using several gene ontology annotations, and curated gene sets associated with mouse phenotype-knockout studies.Measurements: Computationally top-ranked candidate genes and literature-curated genes were included in pathway enrichment analyses. Hierarchical clustering was used to visualize select functional enrichment results between the two phenotypes.Main results: Literature review identified 38 training genes associated with postoperative pain and 31 with CPSP. We identified 2610 prioritized novel candidate genes likely associated with acute and chronic postsurgical pain, the top 10th percentile jointly enriched (p 0.05; Benjamini-Hochberg correction) several pathways, topmost being cAMP response element-binding protein and ion channel pathways. Heat maps demonstrated enrichment of inflammatory/drug metabolism processes in acute postoperative pain and immune mechanisms in CPSP.Conclusion: High interindividual variability in pain responses immediately after surgery and risk for CPSP suggests genetic susceptibility. Lack of large homogenous sample sizes have led to underpowered genetic association studies. Systems biology can be leveraged to integrate genetic-level data with biologic processes to generate prioritized candidate gene lists and understand novel biological pathways involved in acute postoperative pain and CPSP. Such data would be key to informing future polygenic studies with targeted genome wide profiling. This study demonstrates the utility of functional annotation - based prioritization and enrichment approaches and identifies novel genes and unique/shared biological processes involved in acute and chronic postoperative pain. Results provide framework for future targeted genetic profiling of CPSP risk, to enable preventive and therapeutic approaches.