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EBioMedicine. 2016 Oct;12:227-238. doi: 10.1016/j.ebiom.2016.08.037. Epub 2016 Sep 15.

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

Author information

1
Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
2
Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany; Institute of Medical Systems Biology, Ulm University, Germany.
3
Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece.
4
Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany; Department of Anaesthesiology and Intensive Care Therapy, Jena University Hospital, Jena, Germany.
5
Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Research group Clinical Epidemiology, CSCC, Jena University Hospital, Jena, Germany.
6
Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
7
Institute of Medical Systems Biology, Ulm University, Germany.
8
Department of Internal Medicine, University of Patras, Medical School, Greece.
9
Institute of Clinical Molecular Biology, Christian-Albrechts-Universität Kiel, Kiel, Germany.
10
Institute of Epidemiology, Christian-Albrechts-Universität Kiel, Kiel, Germany.
11
Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute, Jena, Germany; Friedrich Schiller University Jena, Jena, Germany.
12
Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Septomics Research Center Jena, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute, Jena, Germany.
13
Institute of Pharmacology and Toxicology, Ulm University Medical Center, Ulm, Germany.
14
Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Department of Anaesthesiology and Intensive Care Therapy, Jena University Hospital, Jena, Germany.
15
Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany; Institute of Medical Systems Biology, Ulm University, Germany; Friedrich Schiller University Jena, Jena, Germany. Electronic address: hans.kestler@uni-ulm.de.
16
Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany. Electronic address: matthias.platzer@leibniz-fli.de.

Abstract

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.

KEYWORDS:

Classification; Exome; Population stratification; Rare single nucleotide variation; Semantic set covering machine; Sepsis

PMID:
27639823
PMCID:
PMC5078585
DOI:
10.1016/j.ebiom.2016.08.037
[Indexed for MEDLINE]
Free PMC Article

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