Fibrinogen-beta gene haplotype is associated with mortality in sepsis.
OBJECTIVE
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.
Manocha
Sanjay
S
Critical Care Research Laboratories, James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6.
Russell
James A
JA
Sutherland
Ainsley M
AM
Wattanathum
Anan
A
Walley
Keith R
KR
D018806:APACHE; D000328:Adult; D000368:Aged; D000483:Alleles; D000704:Analysis of Variance; D016009:Chi-Square Distribution; D015331:Cohort Studies; D005260:Female; D005340:Fibrinogen / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D020641:Polymorphism, Single Nucleotide; D018805:Sepsis / Q000235:genetics* / Q000401:mortality*
D005340:Fibrinogen