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Lancet Respir Med. 2015 Jan;3(1):53-60. doi: 10.1016/S2213-2600(14)70290-5. Epub 2014 Dec 18.

Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study.

Author information

1
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. Electronic address: anna.rautanen@well.ox.ac.uk.
2
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
3
Imperial College London, London, UK.
4
John Radcliffe Hospital, Oxford, UK.
5
Institute for Medical Biometry, Informatics and Epidemiology (IMBIE) of the University of Bonn, Bonn, Germany.
6
William Harvey Research Institute, Barts and The London School of Medicine Queen Mary University of London, London, UK.
7
Hospital Cochin, Paris, France.
8
School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
9
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
10
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Technische Universität München, Institute of Human Genetics, Munich, Germany.
11
Jena University Hospital and Center for Sepsis Control and Care, Jena, Germany.
12
National Health Service Centre, Budapest, Hungary.
13
University of Torino, Turin, Italy.
14
Medical Faculty of Mazaryk University, Brno, Czech Republic.
15
Tartu University Hospital, Tartu, Estonia.
16
University of Bonn, Bonn, Germany.
17
CIBERES, Vall d'Hebron Institute of Research, Universitat Autonoma de Barcelona, Barcelona, Spain.
18
Joan XXIII University Hospital, Pere Virgili Health Institute, University Rovirai Virgili, Tarragona, Spain.
19
Hadassah Medical Centre, Jerusalem, Israel.
20
Jena University Hospital, Jena, Germany.
21
Section of Experimental Anesthesiology, University Hospital, Ulm, Germany.
22
University of British Columbia, Vancouver, BC, Canada.
23
Department of Anaesthesiology and Pain Medicine, Bern University Hospital, and University of Bern, Switzerland.

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.

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.

PMID:
25533491
PMCID:
PMC4314768
DOI:
10.1016/S2213-2600(14)70290-5
[Indexed for MEDLINE]
Free PMC Article

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