title: Genetic Factors of the Disease Course after Sepsis: A Genome-Wide Study for 28Day Mortality.
abstract: Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction that varies by host genomic factors. We conducted a genome-wide association study (GWAS) in 740 adult septic patients and focused on 28day mortality as outcome. Variants with suggestive evidence for an association (p≤10-5) were validated in two additional GWA studies (n=3470) and gene coding regions related to the variants were assessed in an independent exome sequencing study (n=74). In the discovery GWAS, we identified 243 autosomal variants which clustered in 14 loci (p≤10-5). The best association signal (rs117983287; p=8.16×10-8) was observed for a missense variant located at chromosome 9q21.2 in the VPS13A gene. VPS13A was further supported by additional GWAS (p=0.03) and sequencing data (p=0.04). Furthermore, CRISPLD2 (p=5.99×10-6) and a region on chromosome 13q21.33 (p=3.34×10-7) were supported by both our data and external biological evidence. We found 14 loci with suggestive evidence for an association with 28day mortality and found supportive, converging evidence for three of them in independent data sets. Elucidating the underlying biological mechanisms of VPS13A, CRISPLD2, and the chromosome 13 locus should be a focus of future research activities.
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. Electronic address: andre.scherag@med.uni-jena.de.
authors.forename: André
authors.initials: A
authors.lastname: Scherag
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: 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: Miriam
authors.initials: M
authors.lastname: Kesselmeier
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Genome Analysis, Leibniz Institute on Aging - Fritz Lipmann Institute Jena, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Taudien
authors.affiliation: Genome Analysis, Leibniz Institute on Aging - Fritz Lipmann Institute Jena, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
authors.affiliation: Genome Analysis, Leibniz Institute on Aging - Fritz Lipmann Institute Jena, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Felder
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Genome Analysis, Leibniz Institute on Aging - Fritz Lipmann Institute Jena, Germany; Department of Anesthesiology and Intensive Care Therapy, Jena University Hospital, Jena, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sponholz
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Rautanen
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Adrian V S
authors.initials: AVS
authors.lastname: Hill
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine Queen Mary University of London, London, UK.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Hinds
authors.affiliation: Universitätsklinikum Giessen und Marburg GmbH and Justus-Liebig-Universität Giessen, Giessen, Germany.
authors.forename: Hamid
authors.initials: H
authors.lastname: Hossain
authors.affiliation: Charité - Medizinische Klinik mit Schwerpunkt Infektiologie und Pneumologie, Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute Jena, Jena, Germany; Septomics Research Center Jena, Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kurzai
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Septomics Research Center Jena, Jena, Germany.
authors.forename: Hortense
authors.initials: H
authors.lastname: Slevogt
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: 2nd Department of Critical Care Medicine, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Armaganidis
authors.affiliation: Clinical Trial Centre Leipzig, University of Leipzig, Leipzig, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Trips
authors.affiliation: Medical Department, Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; Medical Department, LIFE Research Center (Leipzig Interdisciplinary Research Cluster of Genetic Factors, Phenotypes and Environment), University of Leipzig, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Scholz
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Center for Clinical Studies, Jena University Hospital, Jena, Germany; Head of Paul-Martini-Clinical Sepsis Research Unit, Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Brunkhorst
mesh_terms: D002874:Chromosome Mapping; D015331:Cohort Studies; D018450:Disease Progression; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009026:Mortality; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D040641:Quantitative Trait Loci; D015203:Reproducibility of Results; D018805:Sepsis / Q000175:diagnosis / Q000235:genetics* / Q000382:microbiology / Q000401:mortality*; D013997:Time Factors
keywords: Exome; Genome-wide association study; Host response; Mortality; Sepsis