Protein C -1641 AA is associated with decreased survival and more organ dysfunction in severe sepsis.
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.


METHODS
Prospective cohorts, gene-association study.


METHODS
Tertiary care medical/surgical intensive care unit.


METHODS
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).


METHODS
Patients were genotyped at protein C -1641 and -1654.


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.
Walley
Keith R
KR
Critical Care Research Laboratories, St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
Russell
James A
JA
D018806:APACHE; D000328:Adult; D000368:Aged; D001955:British Columbia / Q000453:epidemiology; D001026:Coronary Artery Bypass / Q000009:adverse effects; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D017052:Hospital Mortality; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000453:epidemiology / Q000209:etiology*; D017063:Outcome Assessment, Health Care; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011486:Protein C / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000401:mortality*
D015850:Interleukin-6; D011486:Protein C