Genome-wide association study of survival from sepsis due to pneumonia : an observational cohort study
Rautanen, Anna (Wellcome Trust Centre for Human Genetics (Oxford, Regne Unit))
Mills, Tara C. (Wellcome Trust Centre for Human Genetics (Oxford, Regne Unit))
Gordon, Anthony C. (Imperial College London)
Hutton, Paula (John Radcliffe Hospital (Oxford, Regne Unit))
Steffens, Michael (University of Bonn. Institute for Medical Biometry, Informatics and Epidemiology (IMBIE))
Nuamah, Rosamond (Queen Mary University of London. William Harvey Research Institute)
Chiche, Jean-Daniel (Hospital Cochin, Paris, France)
Parks, Tom (Wellcome Trust Centre for Human Genetics (Oxford, Regne Unit))
Chapman, Stephen J. (Wellcome Trust Centre for Human Genetics (Oxford, Regne Unit))
Davenport, Emma E. (Wellcome Trust Centre for Human Genetics (Oxford, Regne Unit))
Elliott, Katherine S. (Wellcome Trust Centre for Human Genetics (Oxford, Regne Unit))
Bion, Julian (University of Birmingham. School of Clinical and Experimental Medicine)
Lichtner, Peter (Institute of Human Genetics, Helmholtz Zentrum München)
Meitinger, Thomas (Technische Universität München. Institute of Human Genetics)
Wienker, Thomas F. (University of Bonn. Institute for Medical Biometry, Informatics and Epidemiology (IMBIE))
Caulfield, Mark (Queen Mary University of London. William Harvey Research Institute)
Mein, Charles (Queen Mary University of London. William Harvey Research Institute)
Bloos, Frank (Jena University Hospital (Alemanya))
Bobek, Ilona (National Health Service Centre, Budapest)
Cotogni, Paolo (University of Torino, Turin, Italy)
Sramek, Vladimir (Medical Faculty of Mazaryk University, Brno)
Sarapuu, Silver (Tartu University Hospital (Tartu, Estònia))
Kobilay, Makbule (University of Bonn)
Ranieri, V Marco (University of Torino)
Rello, Jordi (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Sirgo, Gonzalo (Hospital Universitari Joan XXIII de Tarragona)
Weiss, Yoram G. (Hadassah Medical Centre, Jerusalem, Israel)
Russwurm, Stefan (Jena University Hospital (Alemanya))
Schneider, E. Marion (University Hospital of Ulm (Alemanya))
Reinhart, Konrad (Jena University Hospital (Alemanya))
Holloway, Paul A. H. (Imperial College London)
Knight, Julian C. (University of Oxford)
Garrard, Chris S. (John Radcliffe Hospital (Oxford, Regne Unit))
Russell, James A. (University of British Columbia)
Walley, Keith R. (University of British Columbia)
Stüber, Frank (Bern University Hospital)
Hill, Adrian V S. (University of Oxford. Wellcome Trust Centre for Human Genetics)
Hinds, Charles J. (Queen Mary University of London. William Harvey Research Institute)
Universitat Autònoma de Barcelona

Data:	2015
Resum:	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. 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. 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. 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. European Commission and the Wellcome Trust.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra, i la creació d'obres derivades, sempre que no sigui amb finalitats comercials i que es distribueixin sota la mateixa llicència que regula l'obra original. Cal que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	The Lancet. Respiratory medicine, Vol. 3 (january 2015) , p. 53-60, ISSN 2213-2619

DOI: 10.1016/S2213-2600(14)70290-5
PMID: 25533491

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