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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: European Commission and the Wellcome Trust.

CIBERES Vall d'Hebron Institute of Research Universitat Autonoma de Barcelona Barcelona Spain

Department of Anaesthesiology and Pain Medicine Bern University Hospital and University of Bern Switzerland

Hadassah Medical Centre Jerusalem Israel

Hospital Cochin Paris France

Imperial College London London UK

Institute for Medical Biometry Informatics and Epidemiology of the University of Bonn Bonn Germany

Institute of Human Genetics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Institute of Human Genetics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany; Technische Universität München Institute of Human Genetics Munich Germany

Jena University Hospital and Center for Sepsis Control and Care Jena Germany

Jena University Hospital Jena Germany

Joan XXIII University Hospital Pere Virgili Health Institute University Rovirai Virgili Tarragona Spain

John Radcliffe Hospital Oxford UK

Medical Faculty of Mazaryk University Brno Czech Republic

National Health Service Centre Budapest Hungary

School of Clinical and Experimental Medicine University of Birmingham Birmingham UK

Section of Experimental Anesthesiology University Hospital Ulm Germany

Tartu University Hospital Tartu Estonia

University of Bonn Bonn Germany

University of British Columbia Vancouver BC Canada

University of Torino Turin Italy

Wellcome Trust Centre for Human Genetics University of Oxford Oxford UK

William Harvey Research Institute Barts and The London School of Medicine Queen Mary University of London London UK

Lancet Respir Med. 2015 Jan;3(1):7-8. doi: 10.1016/S2213-2600(14)70307-8. PubMed

Intensive Care Med. 2015 Jul;41(7):1379-81. doi: 10.1007/s00134-015-3829-7. PubMed

Intensive Care Med. 2015 Jul;41(7):1382. doi: 10.1007/s00134-015-3893-z. PubMed

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Kumar G, Kumar N, Taneja A. Nationwide trends of severe sepsis in the 21st century (2000–2007) Chest. 2011;140:1223–1231. PubMed

Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348:1546–1554. PubMed

Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med. 2007;35:1244–1250. PubMed

Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013;41:1167–1174. PubMed

Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–1310. PubMed

Lagu T, Rothberg MB, Shieh MS, Pekow PS, Steingrub JS, Lindenauer PK. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med. 2012;40:754–761. PubMed

Adhikari NK, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the global burden of critical illness in adults. Lancet. 2010;376:1339–1346. PubMed PMC

Quartin AA, Schein RM, Kett DH, Peduzzi PN. Magnitude and duration of the effect of sepsis on survival. Department of Veterans Affairs Systemic Sepsis Cooperative Studies Group. JAMA. 1997;277:1058–1063. PubMed

Storgaard M, Hallas J, Gahrn-Hansen B, Pedersen SS, Pedersen C, Lassen AT. Short- and long-term mortality in patients with community-acquired severe sepsis and septic shock. Scand J Infect Dis. 2013;45:577–583. PubMed

Winters BD, Eberlein M, Leung J, Needham DM, Pronovost PJ, Sevransky JE. Long-term mortality and quality of life in sepsis: a systematic review. Crit Care Med. 2010;38:1276–1283. PubMed

Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369:840–851. PubMed

Visscher PM, Brown MA, McCarthy MI, Yang J. Five years of GWAS discovery. Am J Hum Genet. 2012;90:7–24. PubMed PMC

Sorensen TI, Nielsen GG, Andersen PK, Teasdale TW. Genetic and environmental influences on premature death in adult adoptees. N Engl J Med. 1988;318:727–732. PubMed

Cooke GS, Hill AV. Genetics of susceptibility to human infectious disease. Nat Rev Genet. 2001;2:967–977. PubMed

Gingles NA, Alexander JE, Kadioglu A. Role of genetic resistance in invasive pneumococcal infection: identification and study of susceptibility and resistance in inbred mouse strains. Infect Immun. 2001;69:426–434. PubMed PMC

Chapman SJ, Hill AV. Human genetic susceptibility to infectious disease. Nat Rev Genet. 2012;13:175–188. PubMed

Gordon AC, Lagan AL, Aganna E. TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study. Genes Immun. 2004;5:631–640. PubMed

Stuber F, Udalova IA, Book M. -308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter. J Inflamm. 1995;46:42–50. PubMed

Gordon AC, Waheed U, Hansen TK. Mannose-binding lectin polymorphisms in severe sepsis: relationship to levels, incidence, and outcome. Shock. 2006;25:88–93. PubMed

Sutherland AM, Walley KR, Russell JA. Polymorphisms in CD14, mannose-binding lectin, and Toll-like receptor-2 are associated with increased prevalence of infection in critically ill adults. Crit Care Med. 2005;33:638–644. PubMed

Bone RC, Sibbald WJ, Sprung CL. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101:1481–1483.

Russell JA, Walley KR, Singer J. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358:877–887. PubMed

Bernard GR, Vincent JL, Laterre PF. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709. PubMed

Man M, Close SL, Shaw AD. Beyond single-marker analyses: mining whole genome scans for insights into treatment responses in severe sepsis. Pharmacogenomics J. 2013;13:218–226. PubMed

Laterre PF, Garber G, Levy H. Severe community-acquired pneumonia as a cause of severe sepsis: data from the PROWESS study. Crit Care Med. 2005;33:952–961. PubMed

Han B, Eskin E. Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. Am J Hum Genet. 2011;88:586–598. PubMed PMC

Grambsch PM TT. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika Trust. 1994;81:515–526.

Wattanathum A, Manocha S, Groshaus H, Russell JA, Walley KR. Interleukin-10 haplotype associated with increased mortality in critically ill patients with sepsis from pneumonia but not in patients with extrapulmonary sepsis. Chest. 2005;128:1690–1698. PubMed

Hao QL, Ferris DK, White G, Heisterkamp N, Groffen J. Nuclear and cytoplasmic location of the FER tyrosine kinase. Mol Cell Biol. 1991;11:1180–1183. PubMed PMC

Kim L, Wong TW. Growth factor-dependent phosphorylation of the actin-binding protein cortactin is mediated by the cytoplasmic tyrosine kinase FER. J Biol Chem. 1998;273:23542–23548. PubMed

Xu G, Craig AW, Greer P. Continuous association of cadherin with beta-catenin requires the non-receptor tyrosine-kinase Fer. J Cell Sci. 2004;117:3207–3219. PubMed

Sangrar W, Gao Y, Scott M, Truesdell P, Greer PA. Fer-mediated cortactin phosphorylation is associated with efficient fibroblast migration and is dependent on reactive oxygen species generation during integrin-mediated cell adhesion. Mol Cell Biol. 2007;27:6140–6152. PubMed PMC

Craig AW, Greer PA. Fer kinase is required for sustained p38 kinase activation and maximal chemotaxis of activated mast cells. Mol Cell Biol. 2002;22:6363–6374. PubMed PMC

McCafferty DM, Craig AW, Senis YA, Greer PA. Absence of Fer protein-tyrosine kinase exacerbates leukocyte recruitment in response to endotoxin. J Immunol. 2002;168:4930–4935. PubMed

Qi W, Ebbert KV, Craig AW, Greer PA, McCafferty DM. Absence of Fer protein tyrosine kinase exacerbates endotoxin induced intestinal epithelial barrier dysfunction in vivo. Gut. 2005;54:1091–1097. PubMed PMC

Khajah M, Andonegui G, Chan R, Craig AW, Greer PA, McCafferty DM. Fer kinase limits neutrophil chemotaxis toward end target chemoattractants. J Immunol. 2013;190:2208–2216. PubMed PMC

Kovach MA, Standiford TJ. The function of neutrophils in sepsis. Curr Opin Infect Dis. 2012;25:321–327. PubMed

Mira JP, Cariou A, Grall F. Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA. 1999;282:561–568. PubMed

Clark MF, Baudouin SV. A systematic review of the quality of genetic association studies in human sepsis. Intensive Care Med. 2006;32:1706–1712. PubMed

Davila S, Wright VJ, Khor CC. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nat Genet. 2010;42:772–776. PubMed

Christie JD, Wurfel MM, Feng R. Genome wide association identifies PPFIA1 as a candidate gene for acute lung injury risk following major trauma. PLoS One. 2012;7:e28268. PubMed PMC

Frank AJ, Sheu CC, Zhao Y. BCL2 genetic variants are associated with acute kidney injury in septic shock. Crit Care Med. 2012;40:2116–2123. PubMed PMC