The C-reactive protein (+)1444C/T alteration modulates the inflammation and coagulation response in human endotoxemia.
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 (TNFalpha)], 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 approximately 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 TNFalpha 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.
Marsik
Claudia
C
Departments of Clinical Pharmacology and Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria.
Sunder-Plassmann
Raute
R
Jilma
Bernd
B
Kovar
Florian M
FM
Mannhalter
Christine
C
Wagner
Oswald
O
Rumpold
Helmut
H
Endler
Georg
G
D000328:Adult; D001777:Blood Coagulation; D002097:C-Reactive Protein / Q000235:genetics*; D019446:Endotoxemia / Q000097:blood* / Q000276:immunology / Q000378:metabolism*; D004926:Escherichia coli; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009154:Mutation; D010446:Peptide Fragments / Q000032:analysis; D016133:Polymerase Chain Reaction; D011516:Prothrombin / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D005338:Fibrin Fibrinogen Degradation Products; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C036309:fibrin fragment D; C045879:prothrombin fragment 1.2; D011516:Prothrombin; D002097:C-Reactive Protein