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A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis

Stuber, Frank MD; Petersen, Marc MD; Bokelmann, Frank MD; Schade, Ulrich PhD

Feature Article

Objectives To determine the allele frequency and genotype distribution of a bi-allelic tumor necrosis factor (TNF) gene polymorphism and plasma TNF-alpha concentrations in postoperative intensive care unit (ICU) patients suffering from severe sepsis.

Design Prospective, consecutive entry study of patients with severe sepsis in a postoperative ICU.

Setting University hospital.

Patients Forty patients with diagnosis of severe sepsis, admitted to the ICU between June 1993 and December 1994.

Interventions None.

Measurements and Main Results A 782 basepairs fragment of genomic DNA, including the polymorphic site of the restriction enzyme Ncol within the TNF locus, was amplified by means of polymerase chain reaction. The genotype of each patient was determined after Ncol digestion of the amplified product and subsequent agarose gel electrophoresis. Reading the size of the resulting DNA bands from the agarose gel demonstrated the genotype, as defined by the two alleles TNFB1 and TNFB2. Serial blood samples were drawn every sixth hour during the first 48 hrs and every 12th hour thereafter, for less than equals 96 hrs after diagnosis. TNF-alpha plasma concentrations were detected by an enzyme-linked immunosorbent assay. Assessment of organ dysfunction was performed by calculating a Multiple Organ Failure score.

The overall allele frequency (TNFB1 0.35; TNFB2 0.65) and genotype distribution (TNFB1 homozygotes 10%; TNFB1/TNFB2 heterozygotes 48%; TNFB2 homozygotes 42%) in 40 patients with severe sepsis were comparable with those values found in normal individuals. Development of multiple organ failure occurred in 33 (82.5%) of 40 patients, whereas 23 (57.5%) of 40 patients did not survive. In contrast to the overall allele frequency, nonsurvivors showed a significantly higher prevalence of the allele TNFB2 (p less than .005). Patients homozygous for the allele TNFB2 demonstrated a higher mortality rate than heterozygous (TNFB1/TNFB2) patients (p equals .0022). In addition, patients with TNFB2 homozygotes displayed higher circulating TNF-alpha concentrations as well as higher Multiple Organ Failure scores compared with heterozygous (TNFB1/TNFB2) patients.

Conclusions The bi-allelic Ncol polymorphism within the TNF locus is a genomic marker for patients with increased TNF-alpha response and poor prognosis in severe sepsis. The amount of TNF released in situations of severe infection and sepsis appears to be influenced genetically. TNFB2 homozygous individuals displaying increased circulating TNF plasma concentrations combined with high mortality rate may be included in future studies testing anti-TNF strategies in severe sepsis.

(Crit Care Med 1996; 24:381-384)

From the Clinic for Anesthesiology and Intensive Care Medicine (Drs. Stuber, Petersen, and Bokelmann), Christian-Albrechts-University Kiel; Clinical Research Group Shock and Multiple Organ Failure at the University Hospital (Dr. Schade), Essen. Germany.

This study was supported, in part, by the Deutsche Forschungsgemeinschaft grant Stu 185/2-1.

Address requests for reprints to: Frank Stuber, MD. Klinik fur Anasthesiologie und Operative Intensivmedizin, Christian-Albrechts-Universitat Kiel, Schwanenweg 21, 24105 Kiel, Germany.

© Williams & Wilkins 1996. All Rights Reserved.