C-Reactive Protein (CRP) was first described by Tillett and Frances in 1930, as a serum component present in acutely ill patients that reacted with a specific Streptococcus pneumoniae extract they termed Fraction C.1 Over the past 75 years, much has been learned about this C-reactive substance. For reviews, please see references 2 and 3.
|Figure 1. Three-dimensional structure of human C-Reactive Protein (CRP). CRP is synthesized as a 206 amino acid polypeptide that folds to form a flattened jellyroll structure, which then assembles into a radially symmetrical pentamer.7 Figure provided by Symmation LLC.
The human crp gene is located on chromosome 1q23,4 and consists of two exons and one intron.5,6 CRP is synthesized as a 206 amino acid polypeptide and secreted by hepatocytes as an approximately 23 κDa, non-glycosylated monomer,5,6 which non-covalently associates to form the homopentameric ring structure characteristic of pentraxin family members (Figure 1).7
CRP is the prototypical acute phase protein in humans and is an important mediator of host defense. Normal baseline levels of circulating CRP are low, but increase up to 10,000-fold within hours of inflammation induced by infection or injury. It binds a wide array of extrinsic (bacteria, fungus, parasite, and plant components) and intrinsic (damaged cell membranes, chromatin, histones, and apoptotic cells) ligands, and subsequently activates the classical complement pathway and binds immunoglobulin receptors on phagocytes.2,3
CRP has recently received increased attention as numerous studies have implicated it as a predictive biomarker for cardiovascular disease risk.2,3,8 However, because CRP is a non-specific indicator of inflammation, its levels can be significantly influenced by a number of disease conditions as well as other parameters (Table 1).2 Further, two recent studies describe polymorphisms in the crp gene intron9 and promoter10 that cause perturbations to normal expression levels. The 278 nucleotide crp intron contains a GT-rich segment of 39 nucleotides that has been speculated to form a left-handed helix, or so-called Z-form DNA.5,9 Individuals with particular allele combinations exhibit 2-fold lower baseline CRP levels, perhaps due to DNA structural changes that affect transcription.9 Within the promoter, several polymorphisms were discovered in transcription factor binding E-box sites, all of which resulted in different baseline circulating levels of CRP. These authors assert that the quality and quantity of these E-box elements appears to significantly influence CRP levels.10
Taken together, these studies clearly highlight the enormity of factors that can influence circulating CRP levels. As for the heritable component that contributes to population differences in baseline CRP expression, there seems to be at least two interpretations. First, individual variability in baseline CRP, whether resulting from non-genetic or genetic factors, should be recognized, evaluated, and accounted for when using circulating CRP levels as a predictive biomarker. And second, perhaps these polymorphisms themselves, could serve as biomarkers for inflammatory disease risk.2,3,8,9,10
- Tillett, W.S. & T. Frances, Jr. (1930) J. Exp. Med. 52:561.
- Pepys, M.B. & G.M. Hirschfield (2003) J. Clin. Invest.111:1805.
- Black, S. et al. (2004) J. Biol. Chem. 279:48487.
- Walsh, M.T. et al. (1996) Immunogenetics 44:62.
- Lei, K.-J. et al. (1985) J. Biol. Chem. 260:13377.
- Woo, P. et al. (1985) J. Biol. Chem. 260:13384.
- Thompson, D. et al. (1999) Structure 7:169.
- Frank, R. & R. Hargreaves (2003) Nat. Rev. Drug Disc. 2:566.
- Szalai, A.J. et al. (2002) Genes Immun. 3:14.
- Szalai, A.J. et al. (2005) J. Mol. Med. [Epub ahead of print Mar. 19.].