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Protein C -1641 AA is associated with decreased survival and more organ dysfunction in severe sepsis
Keith R Walley1, James A Russell
1Critical Care Research Laboratories, St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
Insights
The protein C -1641 AA genotype is linked to poorer survival and increased organ dysfunction in severe sepsis patients. This genetic factor also correlates with higher interleukin-6 levels post-cardiac surgery.
Area of Science:
- Genetics
- Critical Care Medicine
- Molecular Biology
Background:
- Protein C is crucial in severe sepsis.
- Genetic variations in protein C, specifically at positions -1641 and -1654, are linked to deep venous thrombosis risk.
- The role of these polymorphisms in sepsis outcomes is not well-defined.
Purpose of the Study:
- To investigate the association between protein C gene polymorphisms (-1641 and -1654) and patient outcomes in severe sepsis.
- To determine if these genetic variations influence survival, organ dysfunction, and systemic inflammation.
Main Methods:
- Prospective gene-association study involving derivation (n=62) and replication (n=402) cohorts of severe sepsis patients.
- A third cohort (n=61) of post-cardiopulmonary bypass patients was used to assess biological plausibility.
- Genotyping for protein C -1641 and -1654 polymorphisms.
Main Results:
- The protein C -1641 AA genotype was significantly associated with decreased 28-day survival in both sepsis cohorts (p < .05).
- This genotype correlated with increased organ dysfunction and systemic inflammation markers in sepsis patients (p < .05).
- In post-cardiopulmonary bypass patients, the -1641 AA genotype showed increased serum interleukin-6 levels (p = .024).
Conclusions:
- The protein C -1641 AA genotype is a significant predictor of reduced survival and heightened organ dysfunction in severe sepsis.
- This genetic variant is associated with increased systemic inflammation and elevated interleukin-6 levels, particularly after cardiopulmonary bypass surgery.
Objective:
Protein C contains an A/G polymorphism at position -1641 and a C/T polymorphism at -1654 associated with risk of deep venous thrombosis. We tested the hypothesis that these polymorphisms are associated with altered outcome in patients having severe sepsis, in which protein C is a central molecule.
Design:
Prospective cohorts, gene-association study.
Setting:
Tertiary care medical/surgical intensive care unit.
Patients:
We first recruited a derivation cohort of patients having severe sepsis (n = 62). A second replication cohort was similarly defined but larger (n = 402). We tested for biological plausibility in a third cohort of post-cardiopulmonary bypass patients (n = 61).
Interventions:
Patients were genotyped at protein C -1641 and -1654.
Measurements And Main Results:
The primary outcome variable was survival in cohorts 1 and 2 and postoperative serum interleukin-6 concentration in cohort 3. Severity of individual organ dysfunctions and systemic inflammation were secondary outcome variables. In the first derivation cohort, the protein C -1641 AA genotype was associated with decreased 28-day survival (p < .05). This finding was confirmed in the much larger replication cohort of patients having severe sepsis (p = .028). In addition, the protein C -1641 AA genotype was associated with significantly more organ dysfunction and more clinical evidence of systemic inflammation (p < .05). Furthermore, the -1641 AA genotype was associated with increased serum interleukin-6 at 4 and 24 hrs after cardiopulmonary bypass (p = .024). There was no association of -1654 A/G with phenotype in any cohort.
Conclusions:
Protein C -1641 AA genotype is associated with decreased survival, more organ dysfunction, and more systemic inflammation in patients having severe sepsis and with increased interleukin-6 levels after cardiopulmonary bypass surgery.
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