Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China; Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing, Jiangsu, China.
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.
Chest. 2021 Mar;159(3):1007-1018. doi: 10.1016/j.chest.2020.10.074. Epub 2020 Nov 12.
ARDS is a devastating syndrome with heterogeneous subtypes, but few causal biomarkers have been identified.
Would multistage Mendelian randomization identify new causal protein biomarkers for ARDS 28-day mortality?
Three hundred moderate to severe ARDS patients were selected randomly from the Molecular Epidemiology of ARDS cohort for proteomics analysis. Orthogonal projections to latent structures discriminant analysis was applied to detect the association between proteins and ARDS 28-day mortality. Candidate proteins were analyzed using generalized summary data-based Mendelian randomization (GSMR). Protein quantitative trait summary statistics were retrieved from the Efficiency and safety of varying the frequency of whole blood donation (INTERVAL) study (n = 2,504), and a genome-wide association study for ARDS was conducted from the Identification of SNPs Predisposing to Altered Acute Lung Injury Risk (iSPAAR) consortium study (n = 534). Causal mediation analysis detected the role of platelet count in mediating the effect of protein on ARDS prognosis.
Plasma insulin-like growth factor binding protein 7 (IGFBP7) moderately increased ARDS 28-day mortality (OR, 1.11; 95% CI, 1.04-1.19; P = .002) per log2 increase. GSMR analysis coupled with four other Mendelian randomization methods revealed IGFBP7 as a causal biomarker for ARDS 28-day mortality (OR, 2.61; 95% CI, 1.33-5.13; P = .005). Causal mediation analysis indicated that the association between IGFBP7 and ARDS 28-day mortality is mediated by platelet count (OR, 1.03; 95% CI, 1.02-1.04; P = .01).
We identified plasma IGFBP7 as a novel causal protein involved in the pathogenesis of ARDS 28-day mortality and platelet function in ARDS, a topic for further experimental and clinical investigation.
ARDS 是一种具有异质性亚群的破坏性综合征，但尚未确定明确的因果生物标志物。
多阶段孟德尔随机化是否能确定 ARDS 28 天死亡率的新的因果蛋白生物标志物？
从 ARDS 的分子流行病学队列中随机选择 300 名中度至重度 ARDS 患者进行蛋白质组学分析。正交投影到潜在结构判别分析用于检测蛋白质与 ARDS 28 天死亡率之间的关联。使用广义汇总数据基于孟德尔随机化（GSMR）分析候选蛋白。从频率变化对全血捐献的效率和安全性（INTERVAL）研究（n=2504）中检索蛋白质定量特征汇总统计数据，并从识别易发生急性肺损伤风险的 SNPs（iSPAAR）联盟研究（n=534）中进行 ARDS 的全基因组关联研究。因果中介分析检测血小板计数在调节蛋白质对 ARDS 预后的影响中的作用。
血浆胰岛素样生长因子结合蛋白 7（IGFBP7）适度增加 ARDS 28 天死亡率（OR，1.11；95%CI，1.04-1.19；P=0.002）。GSMR 分析与其他四种孟德尔随机化方法相结合，揭示 IGFBP7 是 ARDS 28 天死亡率的因果生物标志物（OR，2.61；95%CI，1.33-5.13；P=0.005）。因果中介分析表明，IGFBP7 与 ARDS 28 天死亡率之间的关联由血小板计数介导（OR，1.03；95%CI，1.02-1.04；P=0.01）。
我们确定了血浆 IGFBP7 是一种新的因果蛋白，它与 ARDS 28 天死亡率以及 ARDS 中血小板功能的发病机制有关，这是进一步实验和临床研究的主题。
