Plasma Insulin-like Growth Factor Binding Protein 7 Contributes Causally to ARDS 28-Day Mortality evidence From Multistage Mendelian Randomization
Plasma Insulin-like Growth Factor Binding Protein 7 Contributes Causally to ARDS 28-Day Mortality evidence From Multistage Mendelian Randomization
复制标题
血浆胰岛素样生长因子结合蛋白 7 (IGFBP-7) 导致 ARDS 28 天死亡率：来自多阶段孟德尔随机化的证据。
DOI：
10.1016/j.chest.2020.10.074
复制
发表时间：
2021-03-04
期刊：
影响因子：
9.6
通讯作者：
Christiani, David C.
中科院分区：
文献类型：
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作者：
Dong, Xuesi;Zhu, Zhaozhong;Christiani, David C.
背景：急性呼吸窘迫综合征是一种具有异质性亚型的破坏性综合征，但很少有生物标志物被确定。研究问题：多阶段孟德尔随机化能否确定ARDS 28天死亡率的新致病蛋白生物标志物？研究设计和方法：从ARDS分子流行病学队列中随机抽取300例中重度ARDS患者进行蛋白质组学分析。应用正交投影到潜在结构判别分析检测蛋白质与ARDS 28天死亡率之间的关系。候选蛋白采用基于广义汇总数据的孟德尔随机化（GSMR）进行分析。蛋白质数量性状汇总统计数据来源于不同全血捐献频率（INTERVAL）研究的效率和安全性（n = 2504），并来源于易改变急性肺损伤风险（iSPAAR）联合研究的snp鉴定（n = 534）进行了ARDS的全基因组关联研究。通过因果中介分析，检测血小板计数在蛋白对ARDS预后影响中的中介作用。结果：血浆胰岛素样生长因子结合蛋白7 （IGFBP7）每增加log2中度增加ARDS 28天死亡率（OR, 1.11; 95% CI, 1.04-1.19; P = 0.002）。GSMR分析结合其他四种孟德尔随机化方法显示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是由血小板计数介导的（OR, 1.03; 95% CI, 1.02-1.04; P = 0.01）。解释：我们发现血浆IGFBP7是一种新的致病蛋白，参与ARDS 28天死亡率和ARDS血小板功能的发病机制，这是一个有待进一步实验和临床研究的主题。
BACKGROUND: ARDS is a devastating syndrome with heterogeneous subtypes, but few causal biomarkers have been identified.RESEARCH QUESTION: Would multistage Mendelian randomization identify new causal protein biomarkers for ARDS 28-day mortality?STUDY DESIGN AND METHODS: 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.RESULTS: 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).INTERPRETATION: 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.