C-Reactive Protein: Eighty Years from Discovery to Emergence as a Major Risk Marker for Cardiovascular Disease

C-reactive protein (CRP)1 was discovered in 1930 by William Tillett and Thomas Francis from the Rockefeller University. They described a third serologic fraction, or “fraction C,” that could be isolated from patients infected with pneumococcus that was distinct from previously known capsular polysaccharide and nucleoprotein fractions detectable by specific antibody response (1). A decade later, Oswald Avery and Maclyn McCarty—the research team who originally described the “transforming principle” and the concept that genes are made of DNA—also described CRP as an “acute-phase reactant” that was increased in serum of patients suffering from a spectrum of inflammatory stimuli, including myocarditis and the inflammation associated with rheumatic fever(2)(3)(4). Early clues that this inflammatory biomarker might be linked to atherothrombosis are evident in 2 case reports presented by Gunnar Lofstrom from the State Bacteriologic Laboratory in Stockholm in 1943, in which increases in CRP following acute myocardial infarction are described(5). In the mid 1950s, case series presented by Irving Kroop and others indicated that CRP concentrations consistently increase after coronary ischemia and myocardial necrosis, data that was clinically important, as diagnostic tools for acute coronary syndrome did not yet include creatinine kinase or troponin(6). By the mid 1980s, the work of John Volanakis, Mark Pepys, Irving Kushner, and others had identified CRP as a hepatically derived, nonglycosylated, circulating pentraxin composed of 5 identical subunits arranged with pentameric symmetry that had characteristic calcium-dependent binding to specific ligands, including binding to LDL cholesterol(7)(8)(9)(10)(11)(12)(13). They and other investigators further demonstrated that the bulk of circulating CRP is produced by hepatocytes largely under regulatory control of inflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor-α; that the plasma half-life of CRP is approximately 19 h under …