Elsevier

Journal of Infection

Volume 54, Issue 6, June 2007, Pages 572-577
Journal of Infection

Fibrinogen-beta gene haplotype is associated with mortality in sepsis

https://doi.org/10.1016/j.jinf.2006.10.001Get rights and content

Summary

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.

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.

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