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

Anna Rautanen, Tara C Mills, Anthony C Gordon, Paula Hutton, Michael Steffens, Rosamond Nuamah, Jean-Daniel Chiche, Tom Parks, Stephen J Chapman, Emma E Davenport, Katherine S Elliott, Julian Bion, Peter Lichtner, Thomas Meitinger, Thomas F Wienker, Mark J Caulfield, Charles Mein, Frank Bloos, Ilona Bobek, Paolo Cotogni, Vladimir Sramek, Silver Sarapuu, Makbule Kobilay, V Marco Ranieri, Jordi Rello, Gonzalo Sirgo, Yoram G Weiss, Stefan Russwurm, E Marion Schneider, Konrad Reinhart, Paul A H Holloway, Julian C Knight, Chris S Garrard, James A Russell, Keith R Walley, Frank Stüber, Adrian V S Hill, Charles J Hinds, ESICM/ECCRN GenOSept Investigators, Anna Rautanen, Tara C Mills, Anthony C Gordon, Paula Hutton, Michael Steffens, Rosamond Nuamah, Jean-Daniel Chiche, Tom Parks, Stephen J Chapman, Emma E Davenport, Katherine S Elliott, Julian Bion, Peter Lichtner, Thomas Meitinger, Thomas F Wienker, Mark J Caulfield, Charles Mein, Frank Bloos, Ilona Bobek, Paolo Cotogni, Vladimir Sramek, Silver Sarapuu, Makbule Kobilay, V Marco Ranieri, Jordi Rello, Gonzalo Sirgo, Yoram G Weiss, Stefan Russwurm, E Marion Schneider, Konrad Reinhart, Paul A H Holloway, Julian C Knight, Chris S Garrard, James A Russell, Keith R Walley, Frank Stüber, Adrian V S Hill, Charles J Hinds, ESICM/ECCRN GenOSept Investigators

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.

Copyright © 2015 Rautanen et al. Open Access article distributed under the terms of CC-BY-NC-SA. Published by .. All rights reserved.

Figures

Figure 1
Figure 1
Patient cohorts, samples, genotyping, and analysis SNP=single nucleotide polymorphism. HRMA=high-resolution melting curve analysis. QC=quality control.
Figure 2
Figure 2
Manhattan plot for the meta-analysis of 28 day survival in patients with sepsis due to pneumonia (additive model) SNPs with minor allele frequency higher than 2%, information value higher than 0·8, and Hardy-Weinberg equilibrium p higher than 1×10−10 are included (5 888 277 SNPs in total). The region including the FER gene is highlighted in red.
Figure 3
Figure 3
Regional association plot for the chromosome 5 locus (rs4957796) in the meta-analysis of 28 day survival in patients with sepsis due to pneumonia (additive model) Colours indicate the correlation (r2 in CEU [Utah residents with northern or western European ancestry] 1000 Genomes data) with the top SNP rs4957796.
Figure 4
Figure 4
Forest plot for FER SNP rs4957796 in separate cohorts and combined in the meta-analysis of 28 day survival in patients with sepsis due to pneumonia (additive model) ORs (95% CIs) and number of deaths and C and T allele counts in non-survivors and survivors are shown.
Figure 5
Figure 5
Cumulative percentage death rates in patients with sepsis caused by pneumonia according to FER rs4957796 genotype (A) All cohorts combined followed up until 28 days from ICU admission. (B) Directly genotyped GenOSept/GAinS discovery and additional GAinS cohorts followed up until 6 months from ICU admission.

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