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

Kornblit B, Munthe-Fog L, Madsen HO, Strøm J, Vindeløv L, Garred P - Crit Care (2008)

Bottom Line: Whether genetic variation in the human HMGB1 gene is associated with disease susceptibility is unknown.Outcome parameters according to different HMGB1 genotypes were compared.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).

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Affiliation: Department of Clinical Immunology - 7631, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen O, Denmark. brian.kornblit@rh.regionh.dk

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.

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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.
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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.

Mentions: Stratification of the patients according to HMGB1 genotype revealed a significantly lower overall survival in patients with the -1377delAA/- or -1377delA-/- genotypes as compared with patients with the -1377delAA/A genotype (15% versus 44%, P = 0.01) (Figure 2a). For statistical purposes, the one patient homozygous for -1377delA-/- was included in the -1377delAA/- group in all analyses. The decreased overall survival in patients with the -1377delAA/- or -1377delA-/- genotypes was discernible in the survival curves after approximately day 50 (Figure 2a), but did not become significant until the end of follow-up. In Cox regression analysis, the -1377delAA/- or -1377delA-/- genotype was an independent risk factor significantly associated with death, in both a restricted survival model and in an expanded model, including known factors associated with survival (age and number of SIRS criteria) (Table 5).


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

Kornblit B, Munthe-Fog L, Madsen HO, Strøm J, Vindeløv L, Garred P - Crit Care (2008)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2481482&req=5

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.
Mentions: Stratification of the patients according to HMGB1 genotype revealed a significantly lower overall survival in patients with the -1377delAA/- or -1377delA-/- genotypes as compared with patients with the -1377delAA/A genotype (15% versus 44%, P = 0.01) (Figure 2a). For statistical purposes, the one patient homozygous for -1377delA-/- was included in the -1377delAA/- group in all analyses. The decreased overall survival in patients with the -1377delAA/- or -1377delA-/- genotypes was discernible in the survival curves after approximately day 50 (Figure 2a), but did not become significant until the end of follow-up. In Cox regression analysis, the -1377delAA/- or -1377delA-/- genotype was an independent risk factor significantly associated with death, in both a restricted survival model and in an expanded model, including known factors associated with survival (age and number of SIRS criteria) (Table 5).

Bottom Line: Whether genetic variation in the human HMGB1 gene is associated with disease susceptibility is unknown.Outcome parameters according to different HMGB1 genotypes were compared.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).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical Immunology - 7631, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen O, Denmark. brian.kornblit@rh.regionh.dk

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.

Show MeSH
Related in: MedlinePlus