摘要
寻求预防急性病毒性呼吸道传染病(acute viral respiratory infection,ARI)的新策略是减轻全球疾病负担的重要环节.遗传关联研究有利于识别疾病易感风险因素,遗传证据有利于加速药物获得上市批准.当前尚未见通过多组学遗传关联分析揭示ARI易感风险、识别新型药物靶点的研究.该研究旨在揭示跨人群新型ARI易感风险位点,筛选靶向ARI易感风险位点的潜在中药,助力中医药深度融入ARI的预防.首先,以流行性感冒及新型冠状病毒感染(COVID-19)为例,整合蛋白质组、基因组、转录组、DNA甲基化组、RNA可变剪切组数据,通过蛋白质组范围的孟德尔随机化、基于基因的关联分析、全转录组关联分析、SMR 与 HEIDI分析筛选欧洲人群、东亚人群、南亚人群的ARI易感风险靶点.然后,通过SNPnexus对关键ARI易感风险靶点进行保守性与生物学功能分析.最后,通过可药性分析、全表型组关联分析等探索关键易感风险靶点的可药性,筛选靶向可药性关键易感风险位点的潜在中药.该研究识别出COL15A1 为欧洲人群罹患流行性感冒的关键易感风险位点,MAN1A2、RAB1A为东亚人群罹患COVID-19 的关键易感风险位点,PPIE、MFGE8、VWA2、FCER2、TREML2、BMP8B、U2AF1L4、IGFLR1 为南亚人群罹患COVID-19 的关键易感风险位点,ABO为欧洲人群罹患COVID-19 的关键易感风险位点.关键易感风险位点的突变有害程度较高,具有较高致病性.关键易感风险位点主要具有调控免疫系统中的信号因子转导、白细胞介素家族信号传导的生物学功能,部分位点亦具有调控凝血级联反应、血小板活化及信号传导和聚集的功能.COL15A1、MAN1A2、RAB1A、PPIE、MFGE8、VWA2、FCER2、TREML2、BMP8B、ABO可作为ARI的预防用药靶点.益气填精药是靶向关键易感风险位点的主要潜在药物.该研究为ARI易感风险位点的识别提供了新的研究思路与新型中医药预防策略.
Abstract
The investigation of new strategies to prevent acute viral respiratory infections(ARI)is essential for reducing the global disease burden.Genetic association studies are valuable in identifying the susceptibility risk factors for diseases,and genetic evidence can expedite drug approval.To date,few studies have been conducted to reveal the susceptibility risks of ARI and identify novel drug targets through multi-omics genetic association analysis.This study aimed to integrate traditional Chinese medicine(TCM)into ARI prevention by identifying novel susceptibility risk loci across multi-ancestry populations and screening potential traditional Chinese medicines targeting these loci.First,with influenza and coronavirus disease 2019(COVID-19)as examples,the data of proteomics,genomics,transcriptomics,DNA methylation,and RNA alternative splicing were integrated to screen the susceptibility risk loci for ARI in European,East Asian,and South Asian populations.The screening was conducted by proteome-wide Mendelian randomization,gene-based association analyses,transcriptome-wide association analyses,and SMR&HEIDI methods.Then,SNPnexus was used to analyze the conservation and biological functions of key susceptibility risk targets for ARI.The druggability of these targets was explored by druggability analysis and phenome-wide association analysis.Potential traditional Chinese medicines targeting the druggable key susceptibility risk loci were screened.Results showed that COL15A1 was a key susceptibility risk locus for influenza in European populations.MAN1A2 and RAB1A were identified as key susceptibility risk loci for COVID-19 in East Asian populations,while PPIE,MFGE8,VWA2,FCER2,TREML2,BMP8B,U2AF1L4,and IGFLR1 were identified as key susceptibility risk loci for COVID-19 in South Asian populations.In European populations,ABO was a key susceptibility risk locus for COVID-19.The mutations in these loci were highly deleterious and pathogenic.These loci mainly regulated the signaling pathways in the immune system,interleukin family,and some regulated the coagulation cascade,platelet activation,signaling,and aggregation.COL15A1,MAN1A2,RAB1A,PPIE,MFGE8,VWA2,FCER2,TREML2,BMP8B,and ABO were potential preventive drug targets for ARI.TCM with the effects of replenishing Qi and supplementing essence had the potential of targeting the key susceptibility risk loci.This study presents a new research idea for identifying susceptibility risk loci of ARI and a novel prevention strategy of ARI with TCM.
基金项目
国家社会科学基金重大项目(18ZDA322)
江苏省卫健委医学科研重点项目(ZD2022068)
江苏省中医药科技发展计划委托研究项目(2022WTZX02)
苏州市科技发展计划(基础研究-医学应用基础)项目(SKYD2023206)
国家级大学生创新训练计划项目(202210315128Z)
南京中医药大学2022年"罗林秀杯"大学生创新训练项目()
南京中医药大学2023年中医药人工智能"揭榜挂帅"项目()
2024年度江苏省中医疫病研究中心开放课题(JSYB2024KF01)
维普
万方数据