Samenvatting

Sepsis is a life-threatening organ dysfunction caused by a dysregulated immune response to infection. It is the number one cause of death in the Intensive Care Unit (ICU), accounting for 6 million casualties every year. Unfortunately, all clinical trials in the last decade failed due to the highly complex and heterogenous pathophysiology of sepsis. Therefore, a shift towards a more individualized treatment approach tailored to the immunological profile of the individual is needed requires a deeper understanding of the genetic mechanisms underlying sepsis heterogeneity and dysregulated immune response. In this study, we integrated genotype, monocyte RNA-Seq and in vivo (IV) cytokine data in order to identify transcriptome profiles or expression quantitative trait loci (eQTL) that can be associated with the degree of inflammation upon a first, and endotoxin tolerance upon a second lipopolysaccharide (LPS, 1 ng/kg) challenge in healthy individuals. Transcriptomics analysis revealed 17,094 genes to significantly differentially express between timepoints T=0 and T=4 of which 566 had an
absolute log2 fold change > 2. Additionally, inter-individual variability in gene expression was observed leading to the identification of 4,629; 3,739 and 922 genome-wide significant eQTLs at T=0, T=4 and log2 fold change T=0/T=4 (DEG), respectively. The DEG-eQTLs were
enriched using the IV cytokine area under the curve (AUC) and 14 expression-cytokine QTLs were identified influencing the expression of 15 genes and in turn IV cytokine response of several cytokines, especially IL-6 and G-CSF. Enriching the eQTLs at T=0 and T=4 using the
IV endotoxin tolerance identified two expression-tolerance QTLs for lnc-LINS-1 and ECE1, which may represent genetic predictors for endotoxin tolerance. This study is one of the first studies using an in vivo approach to elicit an immune response and quantifying the subsequent degree of endotoxin tolerance acquired. Using the results of this study, we added to the relevance of previous ex vivo studies by verifying their findings in human in vivo. We gained unique insight into the genetic and transcriptomic fingerprint of cytokine response upon first, and the degree endotoxin tolerance acquired upon second challenge with LPS. These results could be used in the future to make early predictions for a patients chance to develop sepsis induced immunoparalysis, based on their genetic profile. Further research is required into the involvement of the proposed QTLs as predictors in cytokine response and tolerance acquirement, in order to translate them to clinically viable genetic markers.