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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.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
C-reactive protein (CRP)2 is a recognized acute-phase protein and a very sensitive marker of systemic inflammation and tissue damage (1). A member of the calcium-dependent ligand-binding pentraxin family, CRP binds with highest affinity to phosphocholine residues and is not merely a bystander molecule in inflammation, but an integral part of the innate immune system, actively contributing to host defense during infection. In addition, by binding to apoptotic cells, CRP promotes their opsonization and phagocytosis by macrophages. Because CRP binds to oxidized LDL, VLDL, and phosphadityl choline as well as to damaged cell membranes, it is not surprising that CRP is found in atherosclerotic plaques (2) and in acute myocardial infarction lesions. Recently, increased serum CRP concentrations have been reported to be valuable for the prediction of atherothrombotic events and the outcome of acute coronary syndromes (3). Extensive studies (3)(4) of high-sensitivity CRP (hsCRP) have demonstrated that this inflammation marker independently predicts cardiovascular risk not detected by routine risk markers, adds prognostic information to risk assessment, and predicts long-term cardiovascular risk in individuals with no prior evidence of cardiovascular disease.

CRP serum concentrations are regulated primarily by proinflammatory cytokines that are released after an acute-phase reaction and that induce CRP de novo synthesis in the liver. Serum CRP concentrations begin to rise after ~6 h (5) and are widely used for diagnosis and monitoring of inflammatory diseases.

CRP baseline concentrations are influenced by various chronic microbial infections (6), a proatherogenic metabolic state (7), smoking(8), coffee consumption (9), stress(10), oral contraceptives (11), and menstrual cycle(12).

Baseline CRP serum concentrations seem to be heritable (13). Genetic variations in the interleukin (IL)-6,1 IL-1, tumor necrosis factor alpha (TNF), and CRP genes may influence the induction of CRP synthesis (13)(14).

The human CRP gene is located on chromosome 1q21-q23, within a conserved genetic region that encodes for proteins critical to the immune system and to intercellular communication (6). CRP serum concentrations in acute and chronic inflammation show considerable interindividual variability, and these differences may be partly determined by genetic variation. Indeed, several alterations have been identified, and several small studies have reported that alterations within the CRP gene are associated with plasma CRP concentrations (13)(14)(15). A C/T alteration at position +1444 within the 3' untranslated region of the CRP gene was recently reported to be associated with increased plasma CRP concentrations in 250 study participants (13).

Numerous immune modulatory effects of CRP have been described. We hypothesized that the CRP genotype might influence inflammatory cytokine expression and other markers of inflammatory response such as markers of coagulation activation. Experimental bacterial lipopolysaccharide (LPS) stimulation in healthy individuals has been proven as an excellent in vivo model to study the cytokine cascade underlying inflammation and has been applied in numerous studies (16)(17)(18)(19)(20). We evaluated the use of this standardized model to examine a putative association between the CRP +1444C/T alteration and inflammation or activation of coagulation in experimental LPS-induced endotoxemia.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study participants
The study protocol was approved by the Ethics Committee of the Medical University of Vienna, and all participants gave written informed consent to participate in the study.

We obtained complete data and DNA samples from 91 healthy Caucasian male paid volunteers who had participated in already published and still unpublished clinical trials in which they had received LPS (21)(22)(23)(24).

All participants were nonsmokers, 19–40 years of age, with a body mass index in the 15th to 85th percentile. Determination of health status included a medical history, physical examination, laboratory values, and virus and standard drug screening. Exclusion criteria were regular or recent intake of medications, including nonprescription medications, and clinically relevant abnormal findings in the medical history or laboratory values.

study protocol
The experimental procedures of our LPS infusion studies have been described elsewhere (25). Briefly, volunteers were admitted to the study ward at 0800 h after an overnight fast. Participants were confined to bed rest throughout the entire study period and fasted for 8.5 h after LPS infusion. Participants received an intravenous bolus containing 2 ng/kg LPS (National Reference Endotoxin, Escherichia coli USP Convention Inc.).

blood sampling and analysis
Blood was collected at times determined by the observed kinetics of plasma IL6 and TNF{alpha} in previous trials (25). Blood samples were collected by venipuncture into Becton Dickinson Vacutainer tubes containing EDTA anticoagulant before LPS infusion and thereafter at the times indicated in Fig. 1 . Plasma samples were processed immediately by centrifugation at 2000g at 4 °C for 15 min and stored at –80 °C before analysis. Plasma IL6 and TNF{alpha} were analyzed with a high-sensitivity enzyme immunoassay (R&D-Systems). Plasma concentrations of F1+2 and D-dimer were evaluated by immunoassays (F1+2, Behring, Marburg; D-dimer, Boehringer Mannheim) as described previously (22).


Figure 1
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  		Figure 1. Association of the common CRP +1444C/T alteration on inflammation and coagulation markers as well as body temperature in human experimental endotoxemia.

Effects of endotoxin infusion on TNF{alpha} and IL-6 concentrations, prothrombin fragment F1+2, and body temperature. Volunteers received 2 ng/kg E. coli endotoxin (n = 91). Data are presented as mean (SE) (* P <0.05, **P ≤0.01).

To overcome the narrow measuring interval (0.16–10 ng/L), we analyzed the 2- and 6-h post-LPS samples after adequate dilution. CRP invariably increased 24 h after endotoxin administration and was an integral measure of IL6 bioactivity (26). Therefore, we measured hsCRP with an immunonephelometric test 24 h after LPS infusion (26).

pcr analysis of the crp 1444 alteration
DNA was isolated from EDTA blood by standard procedures. For detection of the +1444C/T variant in the 3'UTR of the CRP gene [rs1130864 in the National Center for Biotechnology Single Nucleotide Polymorphism database (http://www.ncbi.nlm.nih.gov/SNP)], the principle of mutagenic separated PCR was adapted as described (27)(28).

Mutagenic separated PCR is a single-tube PCR-based technique relying on allele-specific primers that differ in length by 9 bp, resulting in PCR products of different sizes. Single-base mismatches in the allele-specific primers introduce deliberate differences into the allelic PCR products to minimize crossreactions in subsequent cycles. One or 2 different PCR products are amplified, depending on the genotype. PCR products were generated in 25-µL volumes containing 0.65 units of AmpliTaq Gold (Perkin-Elmer Cetus), 1.5 mmol/L MgCl2, 2 µmol/L of each dNTP (Amersham Pharmacia Biotech), 12 pmol CRP 1444 C primer (5'-CGT TAA CTA TGC TGG GAG AC- 3'), 5 pmol CRP 1444 T primer (5'-CTG GGA GCT ATT TAA CTA TGC TGG GTA AT-3'), and 1 pmol common reverse primer (5'-CTT CTC AGC TCT TGC CTT ATG AGT-3'), all synthesized by TIB Molbiol, and ~50 ng DNA. Amplifications were performed in an Eppendorf Thermo Cycler. A 10 min denaturation period at 95 °C was followed by 37 cycles of 95 °C for 45 s, 58 °C for 45 s and 72 °C for 45 s. A final extension step of 7 min at 72 °C completed the reaction. For the CRP 1444 C allele, a 153-bp PCR product and for the CRP 1444 T allele, a 162-bp product were generated and separated on precast 10% Tris-borate-EDTA polyacrylamide gels (Bio-Rad Inc.) for 75 min at 175 V. After being stained with Sybr Green (Molecular Probes) for 20 min, bands were visualized on an ultraviolet transilluminator at 306 nm and photographed.

data analysis
Data are expressed as the mean (SE). After repeated measures ANOVA, we applied nonparametric statistics for robustness. We used the Kruskal Wallis ANOVA for all statistical comparisons between groups, and the Mann–Whitney U-test for post hoc comparisons. All statistical calculations were performed with commercial statistical software (SPSS 10.0, SPSS Inc.).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Of the 91 healthy volunteers who received LPS, 41 (45%) were wild-type homozygous +1444C genotype (CC), 37 (41%) were heterozygous +1444CT (CT), and 13 (14%) were homozygous +1444T (TT).

Genotype frequencies were in Hardy-Weinberg equilibrium in all groups and were similar to those reported previously (13).

effect of crp genotype on basal and stimulated crp concentrations
At baseline, CRP concentrations in C homozygous (CC) individuals were 40% lower than those in T homozygous (TT) individuals (Table 1 ). CRP concentrations showed an upward tendency 24 h after LPS challenge [CC<CT<TT: 22.7 (2) mg/L in CC, 25.0 (3) mg/L in CT, and 33.1 (6) mg/L in TT individuals].


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  		Table 1. CRP+1444 genotype-dependent inflammatory markers in healthy volunteers (n = 91).

association of crp +1444 c/t alteration and inflammation markers
At baseline, before LPS infusion, IL6 basal concentrations in wild-type +1444 CC individuals were 2-fold higher than those in TT individuals (Table 1Up ).

In response to LPS challenge, CC individuals had 2-fold higher peak IL6 concentrations (P <0.01) and higher IL6 release at all time points (P <0.05) than TT carriers (Fig. 1Up ). Similarly, peak TNF{alpha} concentrations were 4-fold higher (P <0.01), and body temperature (P <0.01) was higher in CC than in TT individuals (Fig. 1Up ). Interestingly, basal IL6 concentrations correlated with both peak TNF{alpha} concentrations (r = 0.25, P = 0.03) and IL6 concentrations (r = 0.37, P = 0.001), whereas basal TNF{alpha} concentrations did not correlate with peak concentrations. Monocyte counts, however, did not differ between groups (Table 1Up ).

markers of coagulation activation—association of the +1444 c/t crp alteration
Plasma F1+2 concentrations increased 8-fold 6 h after LPS infusion (P <0.05 vs baseline). Similarly, D-dimer concentrations increased 5-fold, with a maximum at 10 h after LPS infusion (P <0.05 vs baseline). Although peak concentrations did not differ significantly between genotypes, significant differences were seen 24 h after LPS infusion; plasma concentrations of prothrombin fragment F1 + 2 were higher in CC individuals [1.0 (0.1) nmol/L] than in CT individuals [0.7 (0.3) nmol/L at 24 h, P <0.05] and TT carriers [0.6 (0.1) nmol/L at 24 h, P <0.05, Fig. 1Up ]. In parallel, 24 h after LPS infusion, D-dimer concentrations were higher in CC individuals [0.74 (0.1) mg/L] than in TT individuals [0.52 (0.08) mg/L, P <0.05 between groups].

Genotype strata differed particularly in their cytokine response, and to a lesser degree in their coagulation response, to LPS infusion. For all measured variables we observed a consistent gene dosage effect between groups (Fig. 1Up ).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Baseline serum CRP concentrations predict the risk of future myocardial infarction and stroke and reflect a baseline inflammation level (4)(29). Recent studies indicate that, independent of inflammation, genetic variations in the CRP gene, as well as in the IL-6 and IL-1 genes, influence circulating CRP concentrations (14)(30)(31).

Several CRP variants have been associated with interindividual differences in CRP serum concentrations (14)(32)(33). In the healthy young men of our study, baseline CRP concentrations were 64% higher for TT than CC genotype individuals, in agreement with a previous report (14). Similarly, CRP concentrations after LPS challenge were somewhat higher in TT than in CC individuals.

The major novel finding of this study is a hitherto undiscovered association of the CRP +1444 alteration with inflammation, and to a lesser degree, with coagulation. In contrast to CRP, the cytokine release to LPS was severalfold higher in healthy CC individuals than in TT individuals. In CC individuals, released amounts of TNF{alpha}, IL-6, and markers of coagulation activation were significantly higher than in TT individuals (Fig. 1Up , Table 2). Heterozygous individuals exhibited an intermediate response for all variables, supporting the concept of a consistent gene dosage effect. Thus, the +1444 CRP TT genotype associated with the highest basal CRP concentrations was also associated with the lowest measured release of cytokines and coagulation markers, and vice versa. This is noteworthy because CRP release is primarily IL-6–dependent in this model of human endotoxemia (21). The decreased IL-6 release in TT individuals could reflect their lower baseline IL-6 concentrations. It may also reflect lower TNF{alpha} release, because IL-6 concentrations are dependent on TNF action in the LPS infusion model (34)(35). In contrast, the coagulation response is not dependent on TNF or IL-6 in human endotoxemia (21)(35)(36). Therefore, it is possible that a more upstream pathway common to both biological systems is affected.

Considerable recent debate has revolved around whether CRP by itself is causally involved in inflammatory processes and atherogenesis (37), is an innocent bystander(38), or exerts protective antiinflammatory effects (39)(40)(41). In particular, the beneficial effects—Mainz hypothesis—have recently been discussed extensively in the literature (40)(42).

Our results indicate that gene alterations leading to increased CRP expression might have antiinflammatory effects, at least after LPS stimulation. Our observations may also explain why functional genetic alterations within the CRP gene, which lead to increased CRP (e.g., the 1059G/C variant), are not major determinants for cardiovascular risk (43). This paradox may be attributable to the antiinflammatory effects of alteration(s) associated with mildly increased CRP concentrations. It will be interesting to explore whether mildly increased CRP concentrations have antiinflammatory actions. Such studies may become feasible once antagonists of CRP become available for use in clinical trials. Together with previous data (14)(43), our results support the concept that genotype-dependent reference intervals for CRP might increase the predictive power and precision of cardiovascular risk prediction.

limitations of the study
In our trial we studied genotype-dependent CRP expression in healthy young Caucasian males. Our study population included a relatively homogeneous group of healthy, young, nonsmoking, nonobese men. Thus, it was not possible to investigate the modulation of the inflammation response by other variables, including age, menopausal state, ethnic background, body mass index, or smoking, that have been reported to influence the genotype-dependent individual expression of CRP (44). Another limitation of our study was the small sample size and the restriction to 1 inflammatory stimulus, LPS, administered as a single dose. We cannot exclude different results generated in response to other complex multifactorial proinflammatory stimuli over a long time-span that may be present in inflammatory diseases such as arteriosclerosis or diabetes. Finally, we cannot determine whether the examined alteration or another alteration in linkage disequilibrium is causing the marked differences in inflammatory response to LPS challenge.

In conclusion, genetically-determined regulators of CRP concentrations also modulate the individual response to a key inflammatory stimulus, endotoxin. This genetic determination could explain the discrepant results indicating that carriers of CRP gene variants clearly associated with increased basal CRP concentrations such as +1444 CT are not necessarily at an increased risk for cardiovascular disease (43)(45).


   Footnotes
 
1 Human genes: IL-6, interleukin 6; CRP, C-reactive protein, pentraxin-related; TNF, tumor necrosis factor alpha (TNF superfamily, member 2).

2 Nonstandard abbreviations: CRP, C-reactive protein; hsCRP, high-sensitivity C-reactive protein; IL, interleukin; TNF{alpha}, tumor necrosis factor alpha; LPS, lipopolysaccharide; CC, C homozygous; TT, T homozygous.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Hirschfield GM, Pepys MB. C-reactive protein and cardiovascular disease: new insights from an old molecule. QJM 2003;96:793-807.[Abstract/Free Full Text]
  2. Inoue T, Kato T, Uchida T, Sakuma M, Nakajima A, Shibazaki M, et al. Local release of C-reactive protein from vulnerable plaque or coronary arterial wall injured by stenting. J Am Coll Cardiol 2005;46:239-245.[Abstract/Free Full Text]
  3. Cushman M, Arnold AM, Psaty BM, Manolio TA, Kuller LH, Burke GL, et al. C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study. Circulation 2005;112:25-31.[Abstract/Free Full Text]
  4. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998;98:731-733.[Abstract/Free Full Text]
  5. Du Clos TW, Mold C. C-reactive protein: an activator of innate immunity and a modulator of adaptive immunity. Immunol Res 2004;30:261-277.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  6. Black S, Kushner I, Samols D. C-reactive Protein. J Biol Chem 2004;279:48487-48490.[Abstract/Free Full Text]
  7. Libby P, Ridker PM. Inflammation and atherosclerosis: role of C-reactive protein in risk assessment. Am J Med 2004;116(Suppl 6A):9S-16S.
  8. Yen ML, Yang CY, Yen BL, Ho YL, Cheng WC, Bai CH. Increased high sensitivity C-reactive protein and neutrophil count are related to increased standard cardiovascular risk factors in healthy Chinese men. Int J Cardiol 2006;110:191-198.[CrossRef][Medline] [Order article via Infotrieve]
  9. Zampelas A, Panagiotakos DB, Pitsavos C, Chrysohoou C, Stefanadis C. Associations between coffee consumption and inflammatory markers in healthy persons: the ATTICA study. Am J Clin Nutr 2004;80:862-867.[Abstract/Free Full Text]
  10. Melamed S, Shirom A, Toker S, Berliner S, Shapira I. Association of fear of terror with low-grade inflammation among apparently healthy employed adults. Psychosom Med 2004;66:484-491.[Abstract/Free Full Text]
  11. Dreon DM, Slavin JL, Phinney SD. Oral contraceptive use and increased plasma concentration of C-reactive protein. Life Sci 2003;73:1245-1252.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  12. Jilma B, Dirnberger E, Loscher I, Rumplmayr A, Hildebrandt J, Eichler HG, et al. Menstrual cycle-associated changes in blood levels of interleukin 6, alpha1 acid glycoprotein, and C-reactive protein. J Lab Clin Med 1997;130:69-75.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  13. Brull DJ, Serrano N, Zito F, Jones L, Montgomery HE, Rumley A, et al. Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease. Arterioscler Thromb Vasc Biol 2003;23:2063-2069.[Abstract/Free Full Text]
  14. D’Aiuto F, Casas JP, Shah T, Humphries SE, Hingorani AD, Tonetti MS. C-reactive protein (+1444C/T) polymorphism influences CRP response following a moderate inflammatory stimulus. Atherosclerosis 2005;179:413-417.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  15. Suk HJ, Ridker PM, Cook NR, Zee RY. Relation of polymorphism within the C-reactive protein gene and plasma CRP levels. Atherosclerosis 2005;178:139-145.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  16. Hollenstein U, Homoncik M, Stohlawetz PJ, Marsik C, Sieder A, Eichler HG, et al. Endotoxin down-modulates granulocyte colony-stimulating factor receptor (CD114) on human neutrophils. J Infect Dis 2000;182:343-346.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  17. Jilma-Stohlawetz P, Folman CC, von dem Borne AE, Pernerstorfer T, Hollenstein U, Knechtelsdorfer M, et al. Effects of anticoagulation on thrombopoietin release during endotoxemia. J Lab Clin Med 2001;137:64-69.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  18. Fiuza C, Suffredini AF. Human models of innate immunity: local and systemic inflammatory responses. J Endotoxin Res 2001;7:385-388.[CrossRef][ISI]
  19. Martich GD, Boujoukos AJ, Suffredini AF. Response of man to endotoxin. Immunobiology 1993;187:403-416.[ISI][Medline] [Order article via Infotrieve]
  20. Suffredini AF, Hochstein HD, McMahon FG. Dose-related inflammatory effects of intravenous endotoxin in humans: evaluation of a new clinical lot of Escherichia coli O:113 endotoxin. J Infect Dis 1999;179:1278-1282.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  21. Derhaschnig U, Bergmair D, Marsik C, Schlifke I, Wijdenes J, Jilma B. Effect of interleukin-6 blockade on tissue factor-induced coagulation in human endotoxemia. Crit Care Med 2004;32:1136-1140.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  22. Derhaschnig U, Pachinger C, Schweeger-Exeli I, Marsik C, Jilma B. Blockade of GPIIb/IIIa by eptifibatide and tirofiban does not alter tissue factor induced thrombin generation in human endotoxemia. Thromb Haemost 2003;90:1054-1060.[ISI][Medline] [Order article via Infotrieve]
  23. Marsik C, Mayr F, Cardona F, Derhaschnig U, Wagner OF, Jilma B. Endotoxaemia modulates Toll-like receptors on leucocytes in humans. Br J Haematol 2003;121:653-656.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  24. Reiter R, Derhaschnig U, Spiel A, Keen P, Cardona F, Mayr F, et al. Regulation of protease-activated receptor 1 (PAR1) on platelets and responsiveness to thrombin receptor activating peptide (TRAP) during systemic inflammation in humans. Thromb Haemost 2003;90:898-903.[ISI][Medline] [Order article via Infotrieve]
  25. Jilma B, Marsik C, Mayr F, Graninger MT, Taylor FB, Jr, Ribel MC, et al. Pharmacodynamics of active site-inhibited factor VIIa in endotoxin-induced coagulation in humans. Clin Pharmacol Ther 2002;72:403-410.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  26. Derhaschnig U, Pernerstorfer T, Knechtelsdorfer M, Hollenstein U, Panzer S, Jilma B. Evaluation of antiinflammatory and antiadhesive effects of heparins in human endotoxemia. Crit Care Med 2003;31:1108-1112.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  27. Haring D, Endler G, Hsieh K, Mannhalter C. Comparison of methods for determination of interleukin 6 G(-174)C promoter polymorphism. Biotechniques 2002;33:1114-1117.[ISI][Medline] [Order article via Infotrieve]
  28. Rust S, Funke H, Assmann G. Mutagenically separated PCR (MS-PCR): a highly specific one step procedure for easy mutation detection. Nucleic Acids Res 1993;21:3623-3629.[Abstract/Free Full Text]
  29. Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor. Circulation 2004;109(21 Suppl 1):II2-I10.
  30. Westerberg M, Bengtsson A, Ricksten A, Jeppsson A. Tumor necrosis factor gene polymorphisms and inflammatory response in coronary artery bypass grafting patients. Scand Cardiovasc J 2004;38:312-317.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  31. Latkovskis G, Licis N, Kalnins U. C-reactive protein levels and common polymorphisms of the interleukin 1 gene cluster and interleukin 6 gene in patients with coronary heart disease. Eur J Immunogenet 2004;31:207-213.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  32. Eklund C, Lehtimaki T, Hurme M. Epistatic effect of C-reactive protein (CRP) single nucleotide polymorphism (SNP) +1059 and interleukin 1B SNP +3954 on CRP concentration in healthy male blood donors. Int J Immunogenet 2005;32:229-232.[ISI][Medline] [Order article via Infotrieve]
  33. Carlson CS, Aldred SF, Lee PK, Tracy RP, Schwartz SM, Rieder M, et al. Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels. Am J Hum Genet 2005;77:64-77.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  34. Suffredini AF, Reda D, Banks SM, Tropea M, Agosti JM, Miller R. Effects of recombinant dimeric TNF receptor on human inflammatory responses following intravenous endotoxin administration. J Immunol 1995;155:5038-5045.[Abstract]
  35. van der Poll T, Coyle SM, Levi M, Jansen PM, Dentener M, Barbosa K, et al. Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans. Blood 1997;89:3727-3734.[Abstract/Free Full Text]
  36. DeLa Cadena RA, Majluf-Cruz A, Stadnicki A, Tropea M, Reda D, Agosti JM, et al. Recombinant tumor necrosis factor receptor p75 fusion protein (TNFR:Fc) alters endotoxin-induced activation of the kinin, fibrinolytic, and coagulation systems in normal humans. Thromb Haemost 1998;80:114-118.[ISI][Medline] [Order article via Infotrieve]
  37. Li JJ, Fang CH. C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular diseases. Med Hypotheses 2004;62:499-506.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  38. De Servi S, Mariani M, Mariani G, Mazzone A. C-reactive protein increase in unstable coronary disease cause or effect?. J Am Coll Cardiol 2005;46:1496-1502.[Abstract/Free Full Text]
  39. Agrawal A. CRP after 2004. Mol Immunol 2005;42:927-930.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  40. Bhakdi S, Torzewski M, Paprotka K, Schmitt S, Barsoom H, Suriyaphol P, et al. Possible protective role for C-reactive protein in atherogenesis: complement activation by modified lipoproteins halts before detrimental terminal sequence. Circulation 2004;109:1870-1876.[Abstract/Free Full Text]
  41. Volanakis JE. Human C-reactive protein: expression, structure, and function. Mol Immunol 2001;38:189-197.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  42. Kunes P. [C-reactive protein in the pathogenesis of atherosclerosis: advantage and pitfalls of the "Mainz hypothesis"]. Cas Lek Cesk 2005;144:25-31.[Medline] [Order article via Infotrieve]
  43. Zee RY, Ridker PM. Polymorphism in the human C-reactive protein (CRP) gene, plasma concentrations of CRP, and the risk of future arterial thrombosis. Atherosclerosis 2002;162:217-219.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  44. Saito M, Ishimitsu T, Minami J, Ono H, Ohrui M, Matsuoka H. Relations of plasma high-sensitivity C-reactive protein to traditional cardiovascular risk factors. Atherosclerosis 2003;167:73-79.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  45. Miller DT, Zee RY, Suk Danik J, Kozlowski P, Chasman DI, Lazarus R, et al. Association of common CRP gene variants with CRP levels and cardiovascular events. Ann Hum Genet 2005;69:623-638.[CrossRef][ISI][Medline] [Order article via Infotrieve]



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