Genetic Factors of the Disease Course After Sepsis: Rare Deleterious Variants Are Predictive

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. For its clinical course, host genetic factors are important and rare genomic variants are suspected to contribute. We sequenced the exomes of 59 Greek and 15 German patients with bacterial sepsis divided into two groups with extremely different disease courses. Variant analysis was focusing on rare deleterious single nucleotide variants (SNVs). We identified significant differences in the number of rare deleterious SNVs per patient between the ethnic groups. Classification experiments based on the data of the Greek patients allowed discrimination between the disease courses with estimated sensitivity and specificity>75%. By application of the trained model to the German patients we observed comparable discriminatory properties despite lower population-specific rare SNV load. Furthermore, rare SNVs in genes of cell signaling and innate immunity related pathways were identified as classifiers discriminating between the sepsis courses. Sepsis patients with favorable disease course after sepsis, even in the case of unfavorable preconditions, seem to be affected more often by rare deleterious SNVs in cell signaling and innate immunity related pathways, suggesting a protective role of impairments in these processes against a poor disease course. •Rare SNV load is higher in the Greek vs. German population.•Subsets of rare deleterious SNVs are predictive for the disease course after sepsis.•Patients with favorable disease course seem to carry protective deleterious variants in sepsis related pathways. Sepsis is a life-threatening disease caused by improper response to infection. Only little is known about the role of genetic factors. From >4000 patients we selected the most extreme cases showing either a favorable or adverse disease course. We determined rare (75% accuracy. Surprisingly, favorable courses can be expected if defense mechanisms are damaged and prevented from overshooting. This underlines the relevance of rare variants for better understanding of sepsis and may offer new treatment options.