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Plasma sRAGE Acts as Genetically Regulated Causal Intermediate in Sepsis-Associated ARDS.

T. Jones,R. Feng,V. Kerchberger,J. Reilly,B. Anderson,M. Shashaty,Fan Wang,T. Dunn,Thomas R. Riley,J. Abbott,C. Ittner,D. Christiani,C. Mikacenic,M. Wurfel,L. Ware,C. Calfee,M. Matthay,Jason D. Christie,N. Meyer

Published 2019 in American Journal of Respiratory and Critical Care Medicine

ABSTRACT

RATIONALE Acute respiratory distress syndrome (ARDS) lacks known causal biomarkers. Plasma concentrations of the soluble receptor for advanced glycation end products (sRAGE) strongly associate with ARDS risk. However, whether plasma sRAGE contributes causally to ARDS remains unknown. OBJECTIVES Evaluate plasma sRAGE as a causal intermediate in ARDS by Mendelian Randomization (MR), a statistical method to infer causality using observational data. METHODS We measured early plasma sRAGE in two critically ill populations with sepsis. The cohorts were whole genome-genotyped and phenotyped for ARDS. To select validated genetic instruments for MR, we regressed plasma sRAGE on genome-wide genotypes in both cohorts. The causal effect of plasma sRAGE on ARDS was inferred using the top variants with significant associations in both populations (p<0.01, R^2>0.02). We applied the inverse-variance weighted method to obtain consistent estimates of the causal effect of plasma sRAGE on ARDS risk. MEASUREMENTS AND MAIN RESULTS There were 393 European and 266 African ancestry patients in the first cohort and 843 European ancestry patients in the second cohort. Plasma sRAGE was strongly associated with ARDS risk in both populations (OR 1.86; 95% CI [1.54, 2.25]; 2.56 [2.14-3.06] per log increase). Using genetic instruments common to both populations, plasma sRAGE had a consistent causal effect on ARDS risk with a β estimate of 0.50 95% CI [0.09, 0.91] per log increase. CONCLUSIONS Plasma sRAGE is genetically regulated during sepsis, and MR analysis indicates that increased plasma sRAGE leads to increased ARDS risk suggesting plasma sRAGE acts a causal intermediate in sepsis-related ARDS.

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