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Clinical Chemistry 52: 1952-1957, 2006. First published August 17, 2006; 10.1373/clinchem.2006.069823
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(Clinical Chemistry. 2006;52:1952-1957.)
© 2006 American Association for Clinical Chemistry, Inc.

Clinical Immunology

The C-Reactive Protein +1444C/T Alteration Modulates the Inflammation and Coagulation Response in Human Endotoxemia

Claudia Marsik1,2, Raute Sunder-Plassmann2, Bernd Jilma1,4,a, Florian M. Kovar1, Christine Mannhalter2, Oswald Wagner2, Helmut Rumpold2 and Georg Endler2,3

Departments of1 Clinical Pharmacology and2 Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria.
3 Prince Court Medical Center, Kuala Lumpur, Malaysia.
4 Department of Pharmaceutics, College of Pharmacy, University of Gainesville, Gainesville, FL.

aAddress correspondence to this author at: Department of Clinical Pharmacology, Division of Hematology and Immunology, Medical University of Vienna, Vienna, Austria, Waehringer Guertel 18–20, A-1090 Wien, Austria, Europe. Fax. 43-1-40400/2998; e-mail Bernd.Jilma{at}meduniwien.ac.at.

Background: C-reactive protein (CRP) plays a major role in the immune system and is an independent risk marker of cardiovascular disease. However, CRP’s role in atherogenesis as innocent bystander, causative, or even protective agent, remains unresolved. The +1444C/T alteration in the CRP gene has been reported to determine basal CRP concentrations. We hypothesized that this alteration may also be associated with the degree of inflammatory response and coagulation activation in a well-standardized model of systemic inflammation.

Methods: We administered 2 ng/kg endotoxin [Escherichia coli bacterial lipopolysaccharide (LPS)] intravenously to stimulate inflammation in 91 healthy young Caucasian male paid volunteers (age range, 19–40 years). Participants were confined to bed rest and fasted for 8.5 h after LPS infusion. We collected blood samples before LPS infusion and at 0, 2, 6, and 24 h after LPS infusion to measure inflammation markers [interleukin 6 (IL6), tumor necrosis factor-{alpha} (TNF{alpha})], temperature, and coagulation markers (prothrombin fragment F1+2, D-dimer). We analyzed the CRP 3' untranslated variant with a mutagenic separated PCR assay.

Results: Basal concentrations of high-sensitivity CRP were ~40% lower in +1444CC alteration carriers than in T homozygous (TT) allele carriers (P = 0.04). In contrast, basal IL6 concentrations were 2-fold higher in wild-type C homozygous (CC) than in TT individuals (P = 0.01). In response to the LPS challenge, CC individuals had 4-fold higher peak TNF{alpha} concentrations (P <0.01), >2.5-fold higher peak IL6 concentrations (P <0.01), and increased temperature (P <0.01). Twenty-four hours after LPS challenge, prothrombin fragment F1+2 concentrations were 75% higher and D-dimer concentrations 50% higher in CC than in TT individuals (P <0.05).

Conclusions: Genetic factors regulating CRP concentrations also modulate the individual response to endotoxin-stimulated inflammation.




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