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.

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.

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.

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.