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Beyond single-marker analyses: mining whole genome scans for insights into treatment responses in severe sepsis

The Pharmacogenomics Journal volume 13, pages 218–226 (2013)Cite this article

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Abstract

Management of severe sepsis, an acute illness with high morbidity and mortality, suffers from the lack of effective biomarkers and largely empirical predictions of disease progression and therapeutic responses. We conducted a genome-wide association study using a large randomized clinical trial cohort to discover genetic biomarkers of response to therapy and prognosis utilizing novel approaches, including combination markers, to overcome limitations of single-marker analyses. Sepsis prognostic models were dominated by clinical variables with genetic markers less informative. In contrast, evidence for gene–gene interactions were identified for sepsis treatment responses with genetic biomarkers dominating models for predicting therapeutic responses, yielding candidates for replication in other cohorts.

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Acknowledgements

Financial support for this study was provided by Eli Lilly and Company. We thank Michael Bell and Cindy Lee (both Eli Lilly and Company), Duytrac Nguyen (Inventiv Clinical), and Jared Kohler and Angela Prokop (both BioStat Solutions) for assistance in statistical analysis. We also thank Julie Sherman (Eli Lilly and Company) for technical assistance with the illustrations.

Author contribution: Drs Man, Close, Fossceco, Janes, O’Brien and Williams participated in the conception and design of the study. Drs Shaw, Bernard, Douglas, Kaner, Payen, Vincent and Garcia acted as advisors to the study. Dr Man conducted the statistical analysis. Drs Man, Close and Leishman wrote the first draft of the manuscript. All authors reviewed the manuscript critically for intellectual content, read and approved the final version.

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Authors and Affiliations

  1. Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA

    M Man, S Fossceco, J M Janes, A G Leishman & L O'Brien

  2. Department of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA

    S L Close

  3. Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA

    A D Shaw

  4. Division of Allergy, Pulmonary and Critical Care, Vanderbilt University School of Medicine, Nashville, TN, USA

    G R Bernard

  5. Denver Health Medical Center,

    I S Douglas

  6. University of Colorado, School of Medicine, Denver, CO, USA

    I S Douglas

  7. Division of Pulmonary and Critical Care Medicine, Department of Medicine and Genetic Medicine, Weill Cornell Medical College, New York, NY, USA

    R J Kaner

  8. Department of Anesthesiology and Critical Care and SAMU, University Paris 7, Hôpital Lariboisière, 2 rue Ambroise Paré, Paris, France

    D Payen

  9. Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, Brussels, Belgium

    J-L Vincent

  10. Department of Pulmonary and Critical Care Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    M D Williams

  11. Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA

    J G N Garcia

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  1. M Man
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  7. D Payen
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  8. J-L Vincent
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  9. S Fossceco
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Corresponding author

Correspondence to M Man.

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Competing interests

Drs Man, Fossceco, Janes, Leishman, and O’Brien are employees and stockholders of Eli Lilly and Company, and Drs Close and Williams were employees of Eli Lilly and Company at the time of the study. Dr Douglas serves on the academic steering committee for an ongoing study in septic shock sponsored by Eli Lilly and Company. Drs Shaw and Garcia have received consultancy payments from Eli Lilly and Company. Drs Bernard, Kaner, Payen and Vincent have no conflicts relevant to this manuscript to declare.

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Man, M., Close, S., Shaw, A. et al. Beyond single-marker analyses: mining whole genome scans for insights into treatment responses in severe sepsis. Pharmacogenomics J 13, 218–226 (2013). https://doi.org/10.1038/tpj.2012.1

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