title: Association of HMGB1 polymorphisms with outcome in patients with systemic inflammatory response syndrome.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Immunology - 7631, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen O, Denmark. brian.kornblit@rh.regionh.dk
authors.forename: Brian
authors.initials: B
authors.lastname: Kornblit
authors.forename: Lea
authors.initials: L
authors.lastname: Munthe-Fog
authors.forename: Hans O
authors.initials: HO
authors.lastname: Madsen
authors.forename: Jens
authors.initials: J
authors.lastname: Strøm
authors.forename: Lars
authors.initials: L
authors.lastname: Vindeløv
authors.forename: Peter
authors.initials: P
authors.lastname: Garred
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D005091:Exons; D005838:Genotype; D024243:HMGB1 Protein / Q000097:blood* / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007362:Intensive Care Units; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011659:Pulmonary Gas Exchange; D018805:Sepsis / Q000401:mortality; D012720:Severity of Illness Index; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000401:mortality*
chemical_list: D024243:HMGB1 Protein; D010100:Oxygen