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Gene variants of the bactericidal/permeability increasing protein and lipopolysaccharide binding protein in sepsis patients

Gender-specific genetic predisposition to sepsis

Hubacek, Jaroslav A. PhD; Stüber, Frank MD; Fröhlich, Dieter MD; Book, Malte MD; Wetegrove, Silke MD; Ritter, Mirko; Rothe, Gregor MD; Schmitz, Gerd MD

Clinical Investigations
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Objectives To determine whether the genotype frequencies of the five bi-allelic polymorphisms in the bactericidal/permeability increasing protein (BPI) (Lys216 → Glu;Pst I polymorphism in intron 5; silent mutation G545 → C) and the lipopolysaccharide binding protein (LBP) (Cys98 → Gly; Pro436 → Leu) are associated with the incidence and lethality of sepsis.

Design Case control study of patients with sepsis.

Setting Intensive care units within university hospitals.

Patients A total of 204 patients diagnosed with sepsis and 250 healthy blood donors.

Interventions None.

Measurements and Main Results  Short DNA fragments containing the polymorphic sites of the LBP and BPI locus were amplified by the polymerase chain reaction or mismatched polymerase chain reaction. The individual polymorphisms were determined with the appropriate restriction enzyme digestions and subsequent agarose gel electrophoresis. The presence of LBP genotypes with the less frequent Gly98 allele was found to be associated with sepsis (p < .02) in male patients, but not in females. Patients which were homozygote for either of the rare Gly98 (n = 6) and/or Leu436 (n = 5) LBP alleles, furthermore, exclusively were nonsurvivors of sepsis. The genotype frequencies in the BPI gene did not differ between patients and control individuals.

Conclusions Our findings suggest that common polymorphisms in the gene for LBP in combination with male gender are associated with an increased risk for the development of sepsis and, furthermore, may be linked to an unfavorable outcome. These data support the important immunomodulatory role of LBP in Gram-negative sepsis and suggest that genetic testing may be helpful for the identification of patients with an unfavorable response to Gram-negative infection.

From the Institute for Clinical Chemistry and Laboratory Medicine (Drs. Hubacek, Rothe, and Schmitz and Mr. Ritter), the University of Regensburg, Germany; the Department of Anaesthesiology and Intensive Care Medicine (Drs. Stüber, Book, and Wetegrove), Bonn, Germany; the Department of Anaesthesiology (Dr. Fröhlich), the University of Regensburg, Germany; and the Institute of Clinical and Experimental Medicine (Dr. Hubacek), Prague, Czech Republic.

These data support the important immunomodulatory role of lipopolysaccharide binding protein in Gram-negative sepsis and suggest that genetic testing may be helpful for the identification of patients with an unfavorable response to Gram- negative infection.

Address requests for reprints to: Gerd Schmitz, MD, Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauβ-Allee 11, D-93053 Regensburg, Germany. E-mail: gerd.schmitz@klinik.uni-regensburg.de

© 2001 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins