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

Brian Kornblit; Lea Munthe-Fog; Hans O Madsen; Jens Strøm; Lars Vindeløv; Peter Garred

doi:10.1186/cc6935

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

Brian Kornblit, Lea Munthe-Fog, Hans O Madsen, Jens Strøm, Lars Vindeløv, Peter Garred

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

48 Citationer (Scopus)

Abstract

Udgivelsesdato: 2008

Originalsprog	Engelsk
Tidsskrift	Critical Care
Vol/bind	12
Udgave nummer	3
Sider (fra-til)	R83
ISSN	1364-8535
DOI	https://doi.org/10.1186/cc6935
Status	Udgivet - 2008

Bibliografisk note

Keywords: Aged; Case-Control Studies; Exons; Genotype; HMGB1 Protein; Heterozygote; Homozygote; Humans; Intensive Care Units; Middle Aged; Oxygen; Polymorphism, Genetic; Prospective Studies; Pulmonary Gas Exchange; Sepsis; Severity of Illness Index; Systemic Inflammatory Response Syndrome

Adgang til dokumentet

10.1186/cc6935

Citationsformater

@article{420f97d0f68e11ddbf70000ea68e967b,

title = "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.",

author = "Brian Kornblit and Lea Munthe-Fog and Madsen, {Hans O} and Jens Str{\o}m and Lars Vindel{\o}v and Peter Garred",

note = "Keywords: Aged; Case-Control Studies; Exons; Genotype; HMGB1 Protein; Heterozygote; Homozygote; Humans; Intensive Care Units; Middle Aged; Oxygen; Polymorphism, Genetic; Prospective Studies; Pulmonary Gas Exchange; Sepsis; Severity of Illness Index; Systemic Inflammatory Response Syndrome",

year = "2008",

doi = "10.1186/cc6935",

language = "English",

volume = "12",

pages = "R83",

journal = "Critical Care",

issn = "1364-8535",

publisher = "BioMed Central Ltd.",

number = "3",

}

TY - JOUR

T1 - Association of HMGB1 polymorphisms with outcome in patients with systemic inflammatory response syndrome

AU - Kornblit, Brian

AU - Munthe-Fog, Lea

AU - Madsen, Hans O

AU - Strøm, Jens

AU - Vindeløv, Lars

AU - Garred, Peter

N1 - Keywords: Aged; Case-Control Studies; Exons; Genotype; HMGB1 Protein; Heterozygote; Homozygote; Humans; Intensive Care Units; Middle Aged; Oxygen; Polymorphism, Genetic; Prospective Studies; Pulmonary Gas Exchange; Sepsis; Severity of Illness Index; Systemic Inflammatory Response Syndrome

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1186/cc6935

DO - 10.1186/cc6935

M3 - Journal article

C2 - 18577209

SN - 1364-8535

VL - 12

SP - R83

JO - Critical Care

JF - Critical Care

IS - 3

ER -