title: Genetic Factors of the Disease Course After Sepsis: Rare Deleterious Variants Are Predictive.
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.
authors.affiliation: 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.
authors.forename: Stefan
authors.initials: S
authors.lastname: Taudien
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany; Institute of Medical Systems Biology, Ulm University, Germany.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Lausser
authors.affiliation: 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.
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
authors.affiliation: 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.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sponholz
authors.affiliation: 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.
authors.forename: Franziska
authors.initials: F
authors.lastname: Schöneweck
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Felder
authors.affiliation: Institute of Medical Systems Biology, Ulm University, Germany.
authors.forename: Lyn-Rouven
authors.initials: LR
authors.lastname: Schirra
authors.affiliation: Institute of Medical Systems Biology, Ulm University, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Schmid
authors.affiliation: Department of Internal Medicine, University of Patras, Medical School, Greece.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Gogos
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Groth
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-Universität Kiel, Kiel, Germany.
authors.forename: Britt-Sabina
authors.initials: BS
authors.lastname: Petersen
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-Universität Kiel, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Institute of Epidemiology, Christian-Albrechts-Universität Kiel, Kiel, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Huse
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute, Jena, Germany; Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.affiliation: 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.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kurzai
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University Medical Center, Ulm, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Moepps
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University Medical Center, Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gierschik
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.affiliation: 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.
authors.forename: André
authors.initials: A
authors.lastname: Scherag
authors.affiliation: 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.
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.affiliation: Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany. Electronic address: matthias.platzer@leibniz-fli.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002460:Cell Line; D015331:Cohort Studies; D018450:Disease Progression; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D023281:Genomics; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D015203:Reproducibility of Results; D018805:Sepsis / Q000175:diagnosis* / Q000235:genetics* / Q000382:microbiology / Q000401:mortality
keywords: Classification; Exome; Population stratification; Rare single nucleotide variation; Semantic set covering machine; Sepsis