Exploring disease-causing traits for drug repurposing in critically ill COVID-19 patients: A causal inference approach.
Exploring disease-causing traits for drug repurposing in critically ill COVID-19 patients: A causal inference approach.
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DOI：
10.1016/j.isci.2023.108185
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发表时间：
2023-11-17
期刊：
影响因子：
5.8
通讯作者：
Schmidt, Marco F.
中科院分区：
文献类型：
--
作者：
Baukmann, Hannes A.;Cope, Justin L.;Bannard, Colin;Schwinges, Alexander R. E. C.;Lamparter, Margaretha R. J.;Groves, Sarah;Ravarani, Charles N. J.;Amulic, Borko;Klinger, Joern E.;Schmidt, Marco F.
尽管最近开发了预防 SARS-CoV-2 感染的疫苗，但治疗重症 COVID-19 患者仍然是一个重要目标。原则上，全基因组关联研究（GWAS）为重新利用现有药物提供了获取临床证据的捷径；然而，所鉴定的基因常常缺乏致病联系。我们报告了一种寻找药物再利用靶点的替代方法，重点关注直接疾病遗传学之外的致病特征。对一组重症 COVID-19 病例和感染后表现出轻微症状的对照组进行了 60 种血细胞类型、生物化学和体重指数筛查，结果显示高中性粒细胞计数可能是危重疾病的致病特征。我们的方法将 CDK6 和 janus 激酶 (JAK) 抑制剂确定为治疗靶标，并在离体中性粒细胞胞外陷阱 (NET) 形成测定中进行了验证。我们的方法证明了通过利用大型致病性状数据集来增强药物靶点识别的能力。中性粒细胞计数在严重的 COVID-19 疾病进展中起着因果作用 已验证的 CDK6 和 JAK 抑制剂可作为严重的 COVID-19 的治疗目标 大型致病性状数据集增加了药物靶点识别的能力免疫学；微生物学；关联分析
Despite recent development of vaccines to prevent SARS-CoV-2 infection, treatment of critically ill COVID-19 patients remains an important goal. In principle, genome-wide association studies (GWASs) provide a shortcut to the clinical evidence needed to repurpose existing drugs; however, genes identified frequently lack a causal disease link. We report an alternative method for finding drug repurposing targets, focusing on disease-causing traits beyond immediate disease genetics. Sixty blood cell types and biochemistries, and body mass index, were screened on a cohort of critically ill COVID-19 cases and controls that exhibited mild symptoms after infection, yielding high neutrophil cell count as a possible causal trait for critical illness. Our methodology identified CDK6 and janus kinase (JAK) inhibitors as treatment targets that were validated in an ex vivo neutrophil extracellular trap (NET) formation assay. Our methodology demonstrates the increased power for drug target identification by leveraging large disease-causing trait datasets. Neutrophil cell count plays a causal role for severe COVID-19 disease progression Validated CDK6 and JAK inhibitors as treatment targets for severe COVID-19 Large disease-causing trait datasets increase the power of drug target identification Genetics; Immunology; Microbiology; Association analysis
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
7.3
作者：
Hazeldine J;Lord JM
通讯作者：
Lord JM
DOI：
10.1198/016214504000001187
发表时间：
2004-09-01
影响因子：
3.7
作者：
Imai, K;van Dyk, DA
通讯作者：
van Dyk, DA
影响因子：
64.8
作者：
COVID-19 Host Genetics Initiative
通讯作者：
COVID-19 Host Genetics Initiative
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ