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

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.

Figure 1

Schematic illustration of the high mobility group box 1 protein gene locus. The most common inferred haplotypes (frequency > 3%) in both the control population and the systemic inflammatory response syndrome (SIRS) population are shown. Modified from Ferrari and colleagues [41]. Bold, location of polymorphisms; italic, location of mutations; underline, mutations only found in the control population; solid boxes, exons I to V. *Haplotype was statistically more frequent in the SIRS population (P = 0.006) as compared with the control population.

Figure 2

Influence of HMGB1 genotype on survival. (a) Overall survival during the follow-up period according to the -1377delA genotype. (b) 28-day survival according to the 982C>T genotype.