Defining the proinflammatory phenotype using high sensitive C-reactive protein levels as the biomarker.
BACKGROUND
Inflammation is pivotal in atherosclerosis. The prototypic marker of inflammation is C-reactive protein (CRP). Numerous studies have confirmed that high CRP levels in normal volunteers predict cardiovascular events.


OBJECTIVE
The objective of this study was to define proximal and associated abnormalities of the proinflammatory phenotype using CRP levels as the biomarker.


METHODS
Two groups of normal, healthy subjects, selected by stringent criteria from an initial cohort of 252, were studied over the period of 12 months. Group 1 included subjects with consistently low CRP (<0.004 microM or <0.5 mg/liter; low CRP group; n = 15). Group 2 included subjects with consistently high CRP (>2.0 or >0.016 microM to <10 mg/liter or <0.085 microM; high CRP group; n = 13).


METHODS
Fasting blood (50 ml) was obtained, and the following parameters were assayed: high sensitivity CRP, fibrinogen, lipid profile, insulin, whole blood cytokines after stimulation with lipopolysaccharide (LPS; 100 ng/ml for 24 h), soluble cell adhesion molecules, plasminogen activator inhibitor-1, CD40, CD40 ligand, leptin, adiponectin, monocyte chemoattractant protein-1, IL-8, matrix metalloproteinase-3 (MMP-3), and MMP-9. Genomic DNA was obtained from peripheral blood leukocytes, and the TNF-alpha -308 genotype was determined.


RESULTS
The median CRP levels were 0.0018 microM (0.21 mg/liter) and 0.031 microM (3.7 mg/liter) for the low and high groups, respectively. High CRP subjects were older and had significantly higher body mass indexes, triglycerides, insulin, homeostasis model assessment, and leptin levels compared with low CRP subjects. The markers of inflammation, plasminogen activator inhibitor-1, MMP-9, fibrinogen, and vascular cell adhesion molecule-1 levels were significantly higher in the high compared with the low CRP group. LPS-stimulated levels of whole blood IL-1beta, IL-6, and TNF were significantly higher, and IL-4 levels were significantly lower in the high CRP group. After age- and body mass index-adjusted analysis of covariance, only plasma MMP-9 levels and LPS-stimulated whole blood IL-1beta and TNF levels were significantly higher in the high CRP group. The frequency of the rare A allele at TNF-alpha -308 was equivalent in high and low CRP groups.


CONCLUSIONS
A phenotype characterized by increased plasma inflammatory mediators as well as increased LPS-stimulated whole blood TNF-alpha and IL-1beta levels is associated with high plasma CRP levels. This systemic inflammatory phenotype may contribute to vascular inflammation or may reflect inflammation in vessels or at other sites.
Devaraj
Sridevi
S
Laboratory for Atherosclerosis and Metabolic Research, University of California Davis Medical Center, 4635 2nd Avenue, Sacramento, California 95817, USA.
O'Keefe
Grant
G
Jialal
Ishwarlal
I
D000328:Adult; D001161:Arteriosclerosis / Q000097:blood / Q000453:epidemiology / Q000276:immunology*; D015415:Biomarkers / Q000097:blood*; D002097:C-Reactive Protein / Q000378:metabolism*; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000097:blood; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015415:Biomarkers; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein