Keith R Walley1, James A Russell. 1. Critical Care Research Laboratories, St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
Abstract
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.
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.
Authors: B D Freeman; C R Kennedy; H L Frankel; B Clarridge; D Bolcic-Jankovic; E Iverson; E Shehane; A Celious; B A Zehnbauer; T G Buchman Journal: Pharmacogenomics J Date: 2009-12-08 Impact factor: 3.550