Research

Association of HMGB1 polymorphisms with outcome in patients with systemic inflammatory response syndrome

Brian Kornblit^1,2 , Lea Munthe-Fog¹ , Hans O Madsen¹ , Jens Strøm³ , Lars Vindeløv² and Peter Garred¹

¹Department of Clinical Immunology – 7631, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen O, Denmark

²The Allogeneic Hematopoietic Cell Transplantation Laboratory – 4041, Department of Haematology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen O, Denmark

³Department of Research, Sygehus Sønderjylland, University of Southern Denmark, 6200 Aabenraa, Denmark

author email corresponding author email

Critical Care 2008, 12:R83doi:10.1186/cc6935

Published:	24 June 2008

See related commentary by Mollnes, http://ccforum.com/content/12/4/168

Abstract

Introduction

High mobility group box 1 protein (HMGB1) is a pleiotropic cytokine, recently implicated in the pathophysiology of the systemic inflammatory response syndrome (SIRS) and sepsis. Data from experimental sepsis models show that administration of anti-HMGB1 antibodies significantly decreased mortality, even when administration was delayed for 24 hours, providing a window of opportunity for therapeutic intervention if transferred into a clinical setting. Whether genetic variation in the human HMGB1 gene is associated with disease susceptibility is unknown.

Methods

We sequenced the HMGB1 gene in 239 prospectively monitored patients with SIRS admitted to an intensive care unit and we measured the corresponding HMGB1 serum concentrations. Blood donors served as control individuals. Outcome parameters according to different HMGB1 genotypes were compared.

Results

Homozygosity and heterozygosity for a promoter variant (-1377delA) was associated with a decreased overall 4-year survival (15% versus 44%, hazard ratio = 1.80; P = 0.01) and with a decreased number of SIRS criteria. Carriage of an exon 4 variant (982C>T) was significantly associated with an increased number of SIRS criteria, a higher Simplified Acute Physiology Score II score, a lower PaO₂/FiO₂ ratio and lower serum HMGB1 levels (P = 0.01), and with a significantly higher probability of early death due to infection (P = 0.04). HMGB1 was undetectable in the control individuals.

Conclusion

The present article is the first report of clinical implications of variation in the human HMGB1 gene. Two polymorphisms were determined as significant risk factors associated with early and late mortality, which may provide insight into the molecular background of SIRS and sepsis, suggesting a possible role for HMGB1 genetics in future prognostic evaluation.