Dissecting inflammatory complications in critically injured patients by within-patient gene expression changes: a longitudinal clinical genomics study.
PLoS Med
; 8(9): e1001093, 2011 Sep.
Article
en En
| MEDLINE
| ID: mdl-21931541
ABSTRACT
BACKGROUND:
Trauma is the number one killer of individuals 1-44 y of age in the United States. The prognosis and treatment of inflammatory complications in critically injured patients continue to be challenging, with a history of failed clinical trials and poorly understood biology. New approaches are therefore needed to improve our ability to diagnose and treat this clinical condition. METHODS ANDFINDINGS:
We conducted a large-scale study on 168 blunt-force trauma patients over 28 d, measuring â¼400 clinical variables and longitudinally profiling leukocyte gene expression with â¼800 microarrays. Marshall MOF (multiple organ failure) clinical score trajectories were first utilized to organize the patients into five categories of increasingly poor outcomes. We then developed an analysis framework modeling early within-patient expression changes to produce a robust characterization of the genomic response to trauma. A quarter of the genome shows early expression changes associated with longer-term post-injury complications, captured by at least five dynamic co-expression modules of functionally related genes. In particular, early down-regulation of MHC-class II genes and up-regulation of p38 MAPK signaling pathway were found to strongly associate with longer-term post-injury complications, providing discrimination among patient outcomes from expression changes during the 40-80 h window post-injury.CONCLUSIONS:
The genomic characterization provided here substantially expands the scope by which the molecular response to trauma may be characterized and understood. These results may be instrumental in furthering our understanding of the disease process and identifying potential targets for therapeutic intervention. Additionally, the quantitative approach we have introduced is potentially applicable to future genomics studies of rapidly progressing clinical conditions. TRIAL REGISTRATION ClinicalTrials.gov NCT00257231
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Heridas y Lesiones
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Regulación de la Expresión Génica
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Sistema de Señalización de MAP Quinasas
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Inflamación
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Insuficiencia Multiorgánica
Tipo de estudio:
Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Adolescent
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Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
PLoS Med
Asunto de la revista:
MEDICINA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos