• Xuesi Dong, Zhaozhong Zhu, Yongyue Wei, Debby Ngo, Ruyang Zhang, Mulong Du, Hui Huang, Lijuan Lin, Paula Tejera, Li Su, Feng Chen, Amy M Ahasic, B Taylor Thompson, Nuala J Meyer, and David C Christiani.
• 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.
• Chest. 2021 Mar 1; 159 (3): 1007-1018.

BackgroundARDS is a devastating syndrome with heterogeneous subtypes, but few causal biomarkers have been identified.Research QuestionWould multistage Mendelian randomization identify new causal protein biomarkers for ARDS 28-day mortality?Study Design And MethodsThree 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.ResultsPlasma 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).InterpretationWe 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.Copyright © 2021. Published by Elsevier Inc.

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