title: Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study.
abstract: BACKGROUND
  Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival.
  
  
  METHODS
  We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died.
  
  
  RESULTS
  In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10(-8) (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10(-9), after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined.
  
  
  CONCLUSIONS
  We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification.
  
  
  BACKGROUND
  European Commission and the Wellcome Trust.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. Electronic address: anna.rautanen@well.ox.ac.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: Tara C
authors.initials: TC
authors.lastname: Mills
authors.affiliation: Imperial College London, London, UK.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Gordon
authors.affiliation: John Radcliffe Hospital, Oxford, UK.
authors.forename: Paula
authors.initials: P
authors.lastname: Hutton
authors.affiliation: Institute for Medical Biometry, Informatics and Epidemiology (IMBIE) of the University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Steffens
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine Queen Mary University of London, London, UK.
authors.forename: Rosamond
authors.initials: R
authors.lastname: Nuamah
authors.affiliation: Hospital Cochin, Paris, France.
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Chiche
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Parks
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chapman
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Davenport
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Elliott
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Bion
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Technische Universität München, Institute of Human Genetics, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Institute for Medical Biometry, Informatics and Epidemiology (IMBIE) of the University of Bonn, Bonn, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine Queen Mary University of London, London, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Caulfield
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine Queen Mary University of London, London, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Mein
authors.affiliation: Jena University Hospital and Center for Sepsis Control and Care, Jena, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bloos
authors.affiliation: National Health Service Centre, Budapest, Hungary.
authors.forename: Ilona
authors.initials: I
authors.lastname: Bobek
authors.affiliation: University of Torino, Turin, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cotogni
authors.affiliation: Medical Faculty of Mazaryk University, Brno, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Sramek
authors.affiliation: Tartu University Hospital, Tartu, Estonia.
authors.forename: Silver
authors.initials: S
authors.lastname: Sarapuu
authors.affiliation: University of Bonn, Bonn, Germany.
authors.forename: Makbule
authors.initials: M
authors.lastname: Kobilay
authors.affiliation: University of Torino, Turin, Italy.
authors.forename: V Marco
authors.initials: VM
authors.lastname: Ranieri
authors.affiliation: CIBERES, Vall d'Hebron Institute of Research, Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rello
authors.affiliation: Joan XXIII University Hospital, Pere Virgili Health Institute, University Rovirai Virgili, Tarragona, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Sirgo
authors.affiliation: Hadassah Medical Centre, Jerusalem, Israel.
authors.forename: Yoram G
authors.initials: YG
authors.lastname: Weiss
authors.affiliation: Jena University Hospital, Jena, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Russwurm
authors.affiliation: Section of Experimental Anesthesiology, University Hospital, Ulm, Germany.
authors.forename: E Marion
authors.initials: EM
authors.lastname: Schneider
authors.affiliation: Jena University Hospital and Center for Sepsis Control and Care, Jena, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Reinhart
authors.affiliation: Imperial College London, London, UK.
authors.forename: Paul A H
authors.initials: PA
authors.lastname: Holloway
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Knight
authors.affiliation: John Radcliffe Hospital, Oxford, UK.
authors.forename: Chris S
authors.initials: CS
authors.lastname: Garrard
authors.affiliation: University of British Columbia, Vancouver, BC, Canada.
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.affiliation: University of British Columbia, Vancouver, BC, Canada.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Walley
authors.affiliation: Department of Anaesthesiology and Pain Medicine, Bern University Hospital, and University of Bern, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Stüber
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Adrian V S
authors.initials: AV
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
mesh_terms: D015331:Cohort Studies; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011014:Pneumonia / Q000150:complications*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D018805:Sepsis / Q000209:etiology* / Q000235:genetics*; D016019:Survival Analysis
chemical_list: D005819:Genetic Markers; C052602:proto-oncogene protein c-fes-fps; D011505:Protein-Tyrosine Kinases