Alternative titles; symbols
HGNC Approved Gene Symbol: CRP
Cytogenetic location: 1q23.2 Genomic coordinates (GRCh38): 1:159,712,289-159,714,589 (from NCBI)
Oliveira et al. (1979) reported that the CRP protein contains 187 amino acids, but Lei et al. (1985) and Woo et al. (1985) determined that CRP contains an 18-amino acid signal sequence and a mature protein of 206 amino acids.
CRP and serum amyloid P protein (APCS; 104770) are members of the family of proteins known as pentraxins (see 613442). CRP is a ubiquitous protein found in both vertebrates and invertebrates phylogenetically spanning 400 million years of evolution. Originally CRP was defined as a substance, observed in the plasma of patients with acute infections, that reacted with the C polysaccharide of the pneumococcus. It was discovered by Tillett and Francis (1930) and studied by Abernethy and Avery (1941). It is one of the plasma proteins that are called acute phase reactants because of a pronounced rise in concentration after tissue injury or inflammation; in the case of CRP, the rise may be 1000-fold or more. CRP is composed of 5 identical, 21,500-molecular weight subunits. It is detectable on the surface of about 4% of normal peripheral blood lymphocytes. Acute phase reactant CRP is produced in the liver; CRP detectable on lymphocytes is produced by those cells (Kuta and Baum, 1986). Kilpatrick and Volanakis (1991) reviewed the molecular genetics, structure, and function of CRP.
On the basis of in vitro and in vivo experiments, it has been proposed that the function of CRP relates to its ability to recognize specifically foreign pathogens and damaged cells of the host and to initiate their elimination by interacting with humoral and cellular effector systems in the blood. Thus, the CRP molecule has both a recognition and an effector function (Kilpatrick and Volanakis, 1991).
Robey et al. (1984) demonstrated that CRP binds with high affinity to chromatin. It has been proposed that one of its major physiologic functions is to act as a scavenger for chromatin released by dead cells during the acute inflammatory process.
Interleukin-6 (IL6; 147620) and tumor necrosis factor alpha (TNFA; 191160) are inflammatory cytokines and the main inducers of the secretion of C-reactive protein in the liver. CRP is a marker of low-grade inflammation that may have a role in the pathogenesis of atherosclerotic lesions in humans (Blake and Ridker, 2002). The effects of TNF-alpha are mediated by 2 receptors: type 1 (TNFR1; 191190) and type 2 (TNFR2; 191191). The Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) are prospective cohort investigations involving a large number of U.S. female registered nurses and U.S. male health professionals, respectively. Pai et al. (2004) examined plasma levels of soluble TNFR1, soluble TNFR2, interleukin-6, and C-reactive protein as markers of risk for coronary heart disease among women and men participating, respectively, in these 2 studies. Among participants who provided a blood sample and who were free of cardiovascular disease at baseline, 239 women and 265 men had a nonfatal myocardial infarction or fatal coronary heart disease (see 607339) during 8 years and 6 years of follow-up, respectively. Pai et al. (2004) found elevated levels of inflammatory markers, particularly C-reactive protein, indicating an increased risk of coronary heart disease. Although plasma lipid levels were more strongly associated with an increased risk than were inflammatory markers, the level of C-reactive protein was a significant contributor to the prediction of coronary heart disease.
Ridker et al. (2005) addressed the question of whether lowering of C-reactive protein by statins affects clinical outcomes by examining the risk of recurrent myocardial infarction or death from coronary causes among 3,745 patients with acute coronary syndromes. They found that patients who had low CRP levels after statin therapy had better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDL cholesterol. They suggested that strategies to lower cardiovascular risk with statins should include monitoring CRP as well as cholesterol. Similarly, Nissen et al. (2005) studied the relationship between reduced CRP from statin treatment and progression of coronary atherosclerosis. They performed intravascular ultrasonography in 502 patients with angiographically documented coronary disease. The patients were randomly assigned to receive moderate treatment (40 mg of pravastatin orally per day) or intensive treatment (80 mg of atorvastatin orally per day). For patients with coronary artery disease, the reduced rate of progression of atherosclerosis was associated with intensive statin treatment, as compared with moderate statin treatment, and was significantly related to greater reductions in the levels of both atherogenic lipoproteins and CRP.
Using leptin-affinity chromatography, mass spectrometry, and immunochemical analysis, Chen et al. (2006) found that CRP is a major leptin (164160)-interacting protein. In vitro studies showed that human CRP directly inhibited the binding of leptin to its receptor (LEPR; 601007) and blocked cellular signaling. Infusion of human CRP into ob/ob mice blocked the effects of leptin on satiety and weight reduction, and the actions of human leptin were blunted in mice expressing human CRP. Further in vitro studies in human primary hepatocytes showed that physiologic levels of leptin stimulated expression of CRP. Chen et al. (2006) suggested that so-called 'leptin resistance,' which may play a role in obesity, may be mediated by circulating CRP that binds leptin and attenuates its physiologic functions.
Farooqi and O'Rahilly (2007) found no significant differences in CRP levels between 4 congenitally leptin-deficient children and 20 age- and adiposity-matched obese children without leptin deficiency. Mean concentrations of CRP remained unchanged after 2 months and 6 months of daily subcutaneous injections of recombinant human leptin in the children with congenital leptin deficiency. Because leptin repletion in humans congenitally lacking leptin does not increase circulating CRP, Farooqi and O'Rahilly (2007) suggested that the leptin-stimulated increase in CRP mRNA and protein levels in primary human hepatocytes reported by Chen et al. (2006) is unlikely to be physiologically relevant.
Lauer et al. (2011) showed that the tyr402-to-his (Y402H; 134370.0008) polymorphism of factor H (CFH; 134370), which is associated with age-related macular degeneration (ARMD4; 610698), affected surface recruitment by monomeric CRP to specific patches on necrotic retinal pigment epithelial (RPE) cells. Enhanced attachment of the protective Y402 variants of both factor H and FHL1, which is also produced by the CFH gene, by monomeric CRP resulted in more efficient complement control and provided an antiinflammatory environment. Monomeric CRP was generated on the surface of necrotic RPE cells, and this newly formed monomeric CRP colocalized with the cell damage marker ANXA5 (131230). Once bound to the cell surface, the factor H-monomeric CRP complexes allowed complement inactivation and reduced the release of TNF.
Ridker et al. (2002) noted that minor elevations of C-reactive protein are predictive of cardiovascular events in patients with coronary heart disease (see 608320). C-reactive protein not only may be a marker of low-grade chronic systemic inflammation but also may be directly involved in atherosclerosis (Ridker et al., 2001). It can amplify the antiinflammatory response through complement activation, tissue damage, and activation of endothelial cells (Libby et al., 2002).
In a study of 27,939 apparently healthy American women who were followed for a mean of 8 years, Ridker et al. (2002) compared C-reactive protein and low density lipoprotein cholesterol levels in the prediction of first cardiovascular events. These data suggested that the C-reactive protein level is a stronger predictor of cardiovascular events than the high density lipoprotein cholesterol level and that it adds prognostic information to that conveyed by the Framingham risk score.
Long-term treatment with statins is associated with reduced serum C-reactive protein concentration and with improved clinical outcome after acute myocardial infarction. Kobashigawa et al. (1995) showed that use of pravastatin reduced the development of transplant coronary artery disease, and suggested that this may be due in part to a cholesterol-independent effect of statins on immune or inflammatory processes. Labarrere et al. (2002) noted that arterial endothelial expression and raised serum concentrations of the soluble form of intercellular adhesion molecule-1 (ICAM1; 147840) are implicated in development of coronary artery disease after coronary artery bypass surgery. They investigated whether C-reactive protein, known to stimulate ICAM1, was associated with increased ICAM1 concentration and subsequent development of coronary artery disease. They showed a significant correlation between raised concentrations of C-reactive protein and arterial endothelial ICAM1 expression in endomyocardial biopsy samples. They also noted a significant relation between C-reactive protein and soluble ICAM1 concentrations soon after transplantation. Early raised C-reactive protein concentrations were associated with development, increased severity, and enhanced rate of progression of coronary artery disease, and with heightened frequency of ischemic events and graft failure. Labarrere et al. (2002) concluded that C-reactive protein concentration can be used to identify heart transplantation patients at increased risk of coronary artery disease and graft failure and that treatments directed at reduction of C-reactive protein concentration could improve patients' outcomes.
Danesh et al. (2004) reported data from a large study of C-reactive protein and other circulating inflammatory markers, as well as updated metaanalyses, to evaluate their relevance to the prediction of coronary heart disease. They concluded that C-reactive protein is a relatively moderate predictor of coronary heart disease.
In a prospective study of 251 individuals aged 60 or older who had some sign of nonexudative age-related macular dystrophy (ARMD; see 603075), Seddon et al. (2005) found that higher levels of CRP and IL6 were independently associated with progression of ARMD.
In a prospective study of 27,687 women with a mean age of 54.6 years and initially free of ARMD, with a mean follow-up of 10 years, Schaumberg et al. (2007) found that high-sensitivity CRP (hsCRP) and other biomarkers of inflammation predicted incident ARMD. Women with hsCRP levels in the highest vs lowest fifth had a more than 3-fold higher incidence of ARMD. The incidence of ARMD was also increased approximately 2-fold among women with the highest levels of ICAM1 (147840) and fibrinogen (see 134820).
Pepys et al. (2006) reported the design, synthesis, and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by 2 pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP.
Whitehead et al. (1983) isolated a cDNA clone for C-reactive protein from an adult human liver cDNA library. By study of somatic cell hybrids, they mapped the CRP gene to chromosome 1. By in situ hybridization, Floyd-Smith et al. (1985, 1986) localized the CRP gene to 1q21-q23. The APCS gene, with which CRP has about 59% homology, is situated in the same area. Both are pentraxins, a family of proteins with a characteristic discoid arrangement of 5 noncovalently bound subunits.
Floyd-Smith et al. (1986) noted that histone genes (see 142750), which also code for products that interact with DNA, map in the same region of 1q.
Walsh et al. (1996) constructed an approximately 1.4-Mb YAC contig with the CRP and serum amyloid P genes at its core. They gave the order for these and other genes in this area, including SPTA1 (182860), H4F2 (142750), H3F2 (142780), and FCGR1A (146760).
Pseudogenes
Goldman et al. (1987) demonstrated a single CRP pseudogene; the CRP gene itself is single.
Elevated plasma levels of CRP, an inflammation-sensitive marker, were considered an important predictor of future cardiovascular disease (see 607339) and metabolic abnormalities (see 605552) in apparently healthy men and women. Carlson et al. (2005) performed a systematic survey of common nucleotide variation across the genomic region encompassing the CRP gene locus on chromosome 1q21-q23. Of the common single-nucleotide polymorphisms (SNPs) identified, 7 tag SNPs were used to define 8 common haplotypes, which were genotyped in a large cohort study of cardiovascular risk in European American and African American young adults and found to be associated with significant variation in CRP levels (p less than 10(-6)). Carlson et al. (2005) also demonstrated the functional importance of these SNP haplotypes in vitro.
Relative deficiency of pentraxin proteins is implicated in the pathogenesis of systemic lupus erythematosus (SLE; 152700). The C-reactive protein response is defective in patients with acute flares of disease, and mice with targeted deletions of the APCS gene develop a lupus-like illness. CRP maps within an interval linked with SLE (601744). Among 586 simplex SLE families, Russell et al. (2004) found that basal levels of CRP were influenced independently by 2 CRP polymorphisms, which they designated CRP2 (rs1800947) and CRP4 (rs1205) and that the latter was associated with SLE and antinuclear autoantibody production. Russell et al. (2004) hypothesized that defective disposal of potentially immunogenic material may be a contributory factor in lupus pathogenesis.
Broeckel et al. (2007) studied 1,046 individuals from 513 Western European families ascertained for myocardial infarction and found that 31% of the interindividual variation in C-reactive protein levels was explained by genetic factors (p = 0.0000015). An autosomal genome scan obtained a multipoint lod score of 3.15 on chromosome 10 at 141 cM (CRPQTL1; 611920). A similar degree of heritability of CRP levels (30%) was observed in an independent population of 758 individuals from 120 French Canadian hypertensive families, and linkage analysis yielded a maximum lod score of 2.65 at D10S1239, which overlapped with the linkage signal in the Western European population.
Ridker et al. (2008) performed a multistage genomewide association study of CRP levels and found significant association with 7 loci: 2 (GCKR, 600824; HNF1A, 142410) were suspected or known to be associated with maturity-onset diabetes of the young (see, e.g., MODY3, 600496), 1 was a gene-desert region on chromosome 12q23,2, and the remaining 4 were in or near LEPR, APOE (107741), IL6R (147880), or the CRP gene itself. Noting that the protein products of 6 of these 7 loci are directly involved in metabolic syndrome, insulin resistance, beta-cell function, weight homeostasis, and/or premature atherothrombosis, Ridker et al. (2008) concluded that variation in several genes involved in metabolic and inflammatory regulation have significant effects on CRP levels.
Reiner et al. (2008) reported an association between common variants of the HNF1A gene and plasma CRP concentrations in 2 independent populations of older adults.
Zacho et al. (2008) studied 10,276 persons from a general population cohort, including 1,786 in whom ischemic heart disease developed (see 607339) and 741 in whom ischemic cerebrovascular disease developed (see 601367), and an additional 31,992 persons from a cross-sectional general population study, of whom 2,521 had ischemic heart disease and 1,483 had ischemic cerebrovascular disease. Finally, Zacho et al. (2008) compared 2,238 patients with ischemic heart disease with 4,474 control subjects and 612 patients with ischemic cerebrovascular disease with 1,224 control subjects. Zacho et al. (2008) measured levels of high-sensitivity CRP and conducted genotyping for 4 CRP polymorphisms and 2 apolipoprotein E polymorphisms. The risk of ischemic heart disease and ischemic cerebrovascular disease was increased by a factor of 1.6 and 1.3, respectively, in persons who had CRP levels above 3 mg per liter, as compared with persons who had CRP levels below 1 mg per liter. Genotype combinations of the 4 CRP polymorphisms rs1205, {dbSNP 1130864}, rs3091244, and rs3093077 were associated with an increase in CRP levels up to 64%, resulting in a theoretically predicted increased risk of up to 32% for ischemic heart disease and up to 25% for ischemic cerebrovascular disease. However, these genotype combinations were not associated with an increased risk of ischemic vascular disease. In contrast, Zacho et al. (2008) found that apolipoprotein E genotypes were associated with both elevated cholesterol levels and increased risk of ischemic heart disease. Zacho et al. (2008) concluded that polymorphisms in the CRP gene are associated with marked increases in CRP levels, but that these are not in themselves associated with an increased risk of ischemic vascular disease.
Rhodes et al. (2008) typed a dense map of CRP SNPs and quantified serum CRP in 594 unrelated African American individuals and used Bayesian model choice analysis to select the combination of SNPs best explaining basal CRP. They found strong support for a triallelic C/T/A upstream promoter (rs3091244) alone, with the T allele acting in an additive manner, with additional support for a model incorporating both rs3091244 and rs12728740; admixture analysis suggested rs12728740 segregated with haplotypes predicted to be of recent European origin. Rhodes et al. (2008) concluded that a single key variant, rs3091244 (or a variant in strong LD with rs3091244), regulates CRP expression in African American individuals; however, they noted that consistent with previous reports, the effect was modest, explaining only 5.20% of CRP variance.
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