OBJECTIVES: Fibrinogen plays a key role in coagulation and inflammation. Transcription of the fibrinogen-beta gene (FGB) is the rate-limiting step in fibrinogen production. Our aim was to determine whether haplotypes of FGB are associated with mortality and organ dysfunction in a cohort of patients with sepsis. METHODS: A prospective cohort of 631 consecutive Caucasian patients with sepsis from a tertiary care medical-surgical ICU were enrolled in a gene association study. Patients were genotyped for three polymorphisms in FGB: -854 G/A, -455 G/A, and +9006 G/A. Haplotypes were inferred using PHASE. The primary outcome was mortality. Secondary outcomes were severity of organ dysfunction as measured by days alive and free (DAF) of organ dysfunction. RESULTS: Haplotype GAA was associated with a significantly lower 28-day mortality (28.9% vs. 36.9% for all other haplotypes, p=0.03). Carriers of two copies of haplotype GAA (vs. one and zero copies) had more DAF of organ dysfunction. In a multivariate analysis, haplotype GAA was an independent predictor for lower mortality (OR=0.66, 95% CI=0.46-0.94, p=0.02). CONCLUSIONS: Haplotype GAA in FGB is associated with lower mortality and lower severity of organ dysfunction. Haplotype GAA encompasses a previously described haplotype -1420A/-854G/-455A/-249C/-148T/+1690G that is associated with higher fibrinogen levels.
OBJECTIVES: Fibrinogen plays a key role in coagulation and inflammation. Transcription of the fibrinogen-beta gene (FGB) is the rate-limiting step in fibrinogen production. Our aim was to determine whether haplotypes of FGB are associated with mortality and organ dysfunction in a cohort of patients with sepsis. METHODS: A prospective cohort of 631 consecutive Caucasian patients with sepsis from a tertiary care medical-surgical ICU were enrolled in a gene association study. Patients were genotyped for three polymorphisms in FGB: -854 G/A, -455 G/A, and +9006 G/A. Haplotypes were inferred using PHASE. The primary outcome was mortality. Secondary outcomes were severity of organ dysfunction as measured by days alive and free (DAF) of organ dysfunction. RESULTS: Haplotype GAA was associated with a significantly lower 28-day mortality (28.9% vs. 36.9% for all other haplotypes, p=0.03). Carriers of two copies of haplotype GAA (vs. one and zero copies) had more DAF of organ dysfunction. In a multivariate analysis, haplotype GAA was an independent predictor for lower mortality (OR=0.66, 95% CI=0.46-0.94, p=0.02). CONCLUSIONS: Haplotype GAA in FGB is associated with lower mortality and lower severity of organ dysfunction. Haplotype GAA encompasses a previously described haplotype -1420A/-854G/-455A/-249C/-148T/+1690G that is associated with higher fibrinogen levels.
Authors: John Arcaroli; Jeff Sankoff; Nianjun Liu; David B Allison; James Maloney; Edward Abraham Journal: Intensive Care Med Date: 2007-11-10 Impact factor: 17.440