Fibrinogen-beta gene haplotype is associated with mortality in sepsis
Introduction
The efficacy of many therapeutic interventions depends on severity of illness and risk of adverse outcomes. For example, the FDA has recommended that treatment with activated Protein C “is indicated for the reduction of mortality in adult patients with severe sepsis who have a high risk of death”.1 The risk of death from infection has a very high heritability component; greater than the heritability of dying of cancer or cardiovascular disease.2 Thus, genotyping could be useful for the identification of patients at high risk of death in order to select appropriate therapeutic interventions.
Fibrinogen plays a key role in determining outcome from sepsis3 and therefore is a reasonable candidate gene to consider. In sepsis, where the link between inflammation and coagulation is an important factor in the development of multi-organ dysfunction,4 higher fibrinogen levels are associated with improved outcome.5 Low fibrinogen levels are associated with increased organ failure and adverse outcome from sepsis.6
The inter-individual variability in the response of fibrinogen to a stress is known to be heritable based on family and twin studies, with 20–50% of the variance in fibrinogen concentration attributable to genetic variation.7, 8 Fibrinogen is encoded on a cluster of three genes located on the long arm of chromosome 4 (4q28).9 The fibrinogen-beta gene (FGB) is the rate-limiting step in synthesis of the gene product (fibrinogen) and therefore has been the focus of studies of the genetic regulation of fibrinogen level.10 Several polymorphisms in the FGB promoter region, including −148 C/T, −455 G/A, and −854 G/A, have been associated with higher plasma fibrinogen levels.7, 11, 12, 13
The role of FGB polymorphisms in critically ill patients with sepsis has not been previously examined. Accordingly we studied the association of FGB variations with mortality and organ dysfunction using a haplotype-based approach.
Section snippets
Materials and methods
This study was approved by the Research Ethics Board of Providence Health Care and the University of British Columbia.
Results
One thousand eighty-six consecutive critically ill patients were screened for inclusion into our study. Of these 852 met the inclusion criteria of sepsis on admission. Six hundred and thirty-one (74%) of those who met the inclusion criteria were Caucasian and used as the final cohort for analysis.
The fibrinogen haplotype tag SNPs −854G/A, −455G/A and +9006G/A were in Hardy–Weinberg equilibrium using the exact test of Guo and Thompson21 (Table 1). The −455 G/A and +9006 G/A polymorphism are in
Discussion
The major finding of our study is that a haplotype of FGB defined by the −854 G/−455 A/+9006 A alleles (haplotype GAA) was associated with a lower mortality and trend towards less organ dysfunction in critically ill patients having sepsis. The presence of this haplotype GAA was an independent predictor of a lower mortality (p = 0.02) in a multiple logistic regression model.
Haplotype GAA marks a group of haplotypes that are clearly different from all other haplotypes in FGB. Using six SNPs (−1420
Acknowledgements
This work was funded by the Canadian Institutes of Health Research (CIHR).
Conflict of interest: No author has a conflict of interest.
References (38)
- et al.
Heritability of clotting factors and the revival of the prothrombotic state
Lancet
(2002) - et al.
Regulation of fibrinogen assembly. Transfection of Hep G2 cells with B beta cDNA specifically enhances synthesis of the three component chains of fibrinogen
J Biol Chem
(1990) - et al.
Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine
Chest
(1992) - et al.
The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults
Chest
(1991) - et al.
Round table conference on clinical trials for the treatment of sepsis. Brussels, March 12–14, 1994
Chest
(1995) Allelic discrimination using fluorogenic probes and the 5′ nuclease assay
Genet Anal
(1999)- et al.
A new statistical method for haplotype reconstruction from population data
Am J Hum Genet
(2001) - et al.
Detection of a complex that associates with the Bbeta fibrinogen G-455-A polymorphism
Blood
(1998) - et al.
Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk
Lancet
(2003) - et al.
Fibrinogen-derived peptide B beta 1-42 is a multidomained neutrophil chemoattractant
Blood
(1988)