C-reactive protein

C-reactive protein, pentraxin-related
CRP drawn from PDB 1B09
Available structures: 1b09, 1gnh, 1lj7
Identifiers
Symbols	CRP; MGC149895; MGC88244; PTX1
External IDs	OMIM: 123260 MGI: 88512 HomoloGene: 476
Gene ontology Molecular function: • binding • calcium ion binding Cellular component: • extracellular region Biological process: • acute-phase response • inflammatory response
RNA expression pattern
More reference expression data
Orthologs
	Human	Mouse
Entrez	1401	12944
Ensembl	ENSG00000132693	ENSMUSG00000037942
Uniprot	P02741	Q542I3
Refseq	NM_000567 (mRNA) NP_000558 (protein)	NM_007768 (mRNA) NP_031794 (protein)
Location	Chr 1: 157.95 - 157.95 Mb	Chr 1: 174.53 - 174.54 Mb
Pubmed search	[3]	[4]

C-reactive protein (CRP) is a plasma protein, an acute phase protein produced by the liver^[1] and by adipocytes.^[2] It is a member of the pentraxin family of proteins.^[1] It is not related to C-peptide or protein C.

History and nomenclature

C-reactive protein was originally discovered by Tillett and Francis in 1930 as a substance in the serum of patients with acute inflammation that reacted with the C polysaccharide of pneumococcus.^[3] Initially it was thought that CRP might be a pathogenic secretion, as it was elevated in people with a variety of illnesses, including carcinomas. Discovery of hepatic synthesis and secretion of CRP closed that debate. It is thought to bind to phosphocholine, thus initiating recognition and phagocytosis of damaged cells.^[1]

Genetics and biochemistry

The CRP gene is located on the first chromosome (1q21-q23). CRP is a 224 residue protein^[4] with a monomer molar mass of 25106 Da. The protein is an annular pentameric disc in shape. Proteins with this type of configuration are known as pentraxins. Native CRP is a bit different as it has 10-subunits making two pentameric discs, with an overall molecular mass of 251060 Da.

Function

CRP is a member of the class of acute phase reactants as its levels rise dramatically during inflammatory processes occurring in the body. This increment is due to a rise in the plasma concentration of IL-6, which is produced predominantly by macrophages^[1] as well as adipocytes.^[2] CRP binds to phosphocholine on microbes. It is thought to assist in complement binding to foreign and damaged cells and enhances phagocytosis by macrophages, which express a receptor for CRP. It is also believed to play another important role in innate immunity, as an early defense system against infections.

CRP rises up to 50,000 fold in acute inflammation, such as infection. It rises above normal limits within 6 hours, and peaks at 48 hours. Its half-life is constant, and therefore its level is mainly determined by the rate of production (and hence the severity of the precipitating cause). Serum amyloid A is a related acute phase marker that responds rapidly in similar circumstances.^[1]

Diagnostic use

CRP is used mainly as a marker of inflammation. Apart from liver failure, there are few known factors that interfere with CRP production.^[1]

Measuring and charting C-reactive protein values can prove useful in determining disease progress or the effectiveness of treatments. Blood, usually collected in a serum-separating tube, is analysed in a medical laboratory or at the point of care.

Various analytical methods are available for CRP determination, such as ELISA, immunoturbidimetry, rapid immunodiffusion and visual agglutination.

Viral infections tend to give a lower CRP level than bacterial infection.

Normal reference ranges for blood tests are less than 5^[5]-6^[6] mg/l.

A high-sensitivity CRP test measures low levels of CRP (see below).

Cardiology diagnostic test

Arterial damage is thought to result from inflammation due to chemical insults. CRP is a general marker for inflammation and infection, so it can be used as a very rough proxy for heart disease risk. Since many things can cause elevated CRP, this is not a very specific prognostic indicator.^[7] Nevertheless, a level above 2.4 mg/l has been associated with a doubled risk of a coronary event compared to levels below 1 mg/l.^[1]

Glycosylation

CRP may have sugars—sialic acid, glucose, galactose and mannose—attached to it (i.e., it gets glycosylated.) In different disease states, one or two amino-acids get lopped off CRP. It retains its activity, but these losses open it up to glycosylation. Different diseases (each of which raise CRP) will add sugars to it in different patterns. The patterns are different across diseases, but similar amongst patients who had the same disease. A 2003 study looked at patients with lupus, leukemia, tuberculosis, leishmaniasis, Cushing's syndrome and bone cancer. (Healthy subjects did not have enough CRP to successfully characterize "normal" CRP.)

Previous work had shown that CRP increased the rate at which a particular parasite could invade blood cells. The study showed that the different CRPs had very different potencies in this regard. The authors speculate that subtyping CRP may give us more insight into heart attack mechanisms. Although this did not demonstrate whether this glycation of CRP was a 'good thing' or a 'bad thing', it offered circumstantial evidence that the differing glycation is part of CRPs mode-of-action.^[8]

Role in cardiovascular disease

Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of diabetes,^[9][10] hypertension and cardiovascular disease. A study of over 700 nurses showed that those in the highest quartile of trans fat consumption had blood levels of C-reactive protein that were 73% higher than those in the lowest quartile.^[11] Although one group of researchers indicated that CRP may only be a moderate risk factor for cardiovascular disease,^[12] this study (known as the Reykjavik Study) was found to have some problems for this type of analysis related to the characteristics of the population studied, and there was an extremely long follow-up time which may have attenuated the association between CRP and future outcomes.^[13] Others have shown that CRP can exacerbate ischemic necrosis in a complement-dependent fashion and that CRP inhibition can be a safe and effective therapy for myocardial and cerebral infarcts; so far, this has only been demonstrated in animal models.^[14]

The JUPITER trial was conducted to determine if patients with elevated high-sensitivity CRP levels but without hyperlipidemia might benefit from statin therapy. Statins were selected because they have been proven to reduce levels of CRP. The trial found that patients taking rosuvastatin with elevated high-sensitivity CRP levels experienced a decrease in the incidence of major cardiovascular events.^[15]

To clarify whether CRP is a bystander or active participant in atherogenesis, a 2008 study compared people with various genetic CRP variants. Those with a high CRP due to genetic variation had no increased risk of cardiovascular disease compared to those with a normal or low CRP.^[16]

High-sensitivity CRP

To measure the CRP level, a "high-sensitivity" CRP or hs-CRP test needs to be performed and analyzed by a laboratory. This is an automated blood test designed for greater accuracy in measuring low levels of CRP, which allows the physician to assess cardiovascular risk. If a result in the low-risk range is found ( < 1 mg/L), it does not need repeating. Higher levels need repeating, and clinical evaluation as necessary.

Role in cancer

The role of inflammation in cancer is not well known. Some organs of the body show greater risk of cancer when they are chronically inflamed.

Blood samples of persons with colon cancer have an average CRP concentration of 2.69 milligrams per liter. Persons without colon cancer average 1.97 milligrams per liter. The difference was statistically significant.^[17] These findings concur with previous studies that indicate that anti-inflammatory drugs could lower colon cancer risk.^[18]

See also

• acute phase
• erythrocyte sedimentation rate
• immunology

Additional images

References

External links

• MedlinePlus Encyclopedia 003356
• Inflammation, Heart Disease and Stroke: The Role of C-Reactive Protein (American Heart Association)
• MeSH C-Reactive+Protein