Proteomics analysis of plasma for risk of sepsis: Findings from the Atherosclerosis Risk in Communities Study

ObjectiveSepsis is a serious condition resulting from infection associated with high mortality. A high-throughput analysis of circulating blood proteins may provide mechanistic insight and potent therapeutic targets for the prevention of sepsis. Patients and MethodsWe used multivariable Cox regression analysis to examine the association of 4,955 plasma proteins measured by SomaScan with the risk of incident sepsis, defined by hospital discharge with a primary diagnosis code for sepsis, among 11,065 participants of the Atherosclerosis Risk in Communities (ARIC) Study (visit 3 in 1993-95; mean age, 60.1 years, 54.4% female, 21.0% Black). Proteins (false discovery rate [FDR] of P <0.05) discovered at visit 3 were replicated using data at visit 5 (n=4,869 in 2011-13: mean age, 75.5 years) and in the Cardiovascular Health Study (CHS) (n=3,512 in 1992-93; mean age, 74.5 years). Canonical pathways were identified by enrichment analyses. ResultsWe identified 669 proteins associated with the risk of sepsis in the ARIC visit 3 cohort. Of those, 175 proteins were significantly associated with sepsis in the visit 5 cohort. Of the 175 proteins, 90 proteins were replicated in an external replication cohort of CHS. The top 20 proteins ranked by P value were relevant to acute inflammatory signaling in innate immunity (e.g., GDF15, EGFR, CNTN1, HDGF, NBL1, TNFRSF1A, TFRSF1B, IL15RA, SLAMF1). Pathway analyses implicated activation of pro-inflammatory pathways (e.g., cytokine storm signaling) as well as inhibition of anti-inflammatory pathways (e.g., Liver X Receptor/Retinoid X Receptor [LXR/RXR] Activation), which also play relevant roles in lipid metabolism. ConclusionsIn this large-scale proteomics analysis, levels of acute inflammatory proteins measured during routine visits were associated with the subsequent incidence of sepsis. An increased risk of sepsis associated with the inhibition of anti-inflammatory pathways, such as LXR/RXR Activation warrants further mechanistic investigation.