A104-06 An Exposome Wide Association Study (ExWAS) of ARDS Phenotypes: 3-HPMA, a Metabolite of the Cellular Toxicant Acrolein, Is Associated With the Hyperinflammatory Phenotype and Mortality

Abstract Rationale Two phenotypes of ARDS are observed with divergent outcomes and treatment responses: hyperinflammatory and hypoinflammatory. Environmental factors impact phenotypes of other diseases (e.g. Th2-high asthma), but it remains unknown whether environmental exposures influence ARDS phenotypes. Exposome-wide association studies (ExWAS) provide a systematic approach to identify relationships between exposures and phenotypes. High-resolution mass spectrometry (MS) enables untargeted measurements of exogenous chemical exposures, xenobiotics. We aimed to: (1) perform an MS-based ExWAS to identify exposures differentially associated with ARDS phenotype, and (2) validate a biologically plausible candidate with targeted measurements. Methods (1)ExWAS/Discovery: We studied 160 ARDS patients from the ROSE cohort with phenotypes derived from an established method of latent class analysis incorporating clinical and plasma protein data (Fig1A). MS was performed on baseline plasma. Peak intensities of xenobiotics were compared between phenotypes using Wilcoxon rank-sum with p-values adjusted for multiple comparisons by FDR. 3-HPMA, a metabolite of the toxicant acrolein, was selected for validation based on a marked increase in hyperinflammatory ARDS and biologic plausibility. (2)Validation: 3-HPMA was quantified in baseline urine using LC-MS/MS from 142 ARDS patients in the EARLI cohort with measured tobacco smoke exposure (acrolein exists in tobacco smoke). Logistic regression tested the association of urine 3-HPMA with phenotype, adjusting for age, sex, smoking and alcohol (Fig1A). To further evaluate clinical relevance, association of plasma 3-HPMA with 28-day mortality was assessed using the same covariates in the ExWAS/Discovery cohort. Results In the ExWAS/Discovery cohort, 45 xenobiotics were significantly increased in hyperinflammatory versus hypoinflammatory ARDS (p-adj0.05, 1 log2FC, Fig1B). The acrolein metabolite 3-HPMA was an outlier in terms of fold-change and statistical significance (log2FC=4, p-adj0.001). Acrolein is a highly reactive aldehyde that causes chemical-induced lung injury in animal studies. Acrolein is an exogenous pollutant in smoke and air pollution and an endogenous toxin produced by neutrophil myeloperoxidase and lipid peroxidation. In the validation cohort, urine 3-HPMA concentration was significantly associated with hyperinflammatory ARDS independent of age, sex, smoking and alcohol (OR 3.05 per 300ng/mg increase, 95%CI 1.57-5.91, p = 0.001; Fig1C). In the ExWAS/Discovery cohort, log(plasma 3-HPMA) was significantly associated with 28-day mortality (OR 1.58 per SD increase, 95%CI 1.12-2.24, p = 0.01). Conclusions 3-HPMA, a metabolite of the cellular toxicant acrolein, was independently associated with hyperinflammatory ARDS and mortality. Acrolein exposure, from both exogenous and endogenous sources, may be a mechanism of injury in ARDS. This abstract is funded by: NIH