Received on March 7, 2006
Accepted on July 26, 2006

Clinical Immunology

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

¹ Departments of Clinical Pharmacology and Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
² Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
³ Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria, and Department of Pharmaceutics, University of Gainesville, Gainesville, FL
⁴ Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
⁵ Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria, and Prince Court Medical Center, Kuala Lumpur, Malaysia

^* To whom correspondence should be addressed. 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- (TNF)], temperature, and coagulation markers (prothrombin fragment F_{1 + 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/T 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 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 F_{1 + 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.