Genetic Study Undermines Case for CRP as Cause of Vascular Disease

October 30, 2008

October 30, 2008 (Copenhagen, Denmark) — Is C-reactive protein (CRP) a promoter of cardiovascular disease or simply a marker of increased cardiovascular risk? Probably the latter, according to the latest study to address the question, in which four gene variants tied to sharply increased CRP levels were shown not to be associated with an elevated CV-event risk [1].

"This finding suggests that the increase in the risk of ischemic vascular disease associated with higher plasma CRP levels observed in epidemiologic studies may not be causal, but rather that increased CRP levels are simply a marker for atherosclerosis and ischemic vascular disease," write the authors, led by Dr Jeppe Zacho (Herlev Hospital, Copenhagen, Denmark).

Their research, based on tens of thousands of predominantly community-based participants from four distinct Danish cohort studies, appears in the October 30, 2008 issue of the New England Journal of Medicine.

An accompanying editorial agrees with the authors [2]. Their findings "strongly indicate that CRP is not causally involved in the pathogenesis of atherosclerotic disease," write Dr Heribert Schunkert (Lubeck University, Germany) and Dr Nilesh J Samani (University of Leicester, UK). "Thus, immediate targeting of CRP is unlikely to be beneficial in reducing the risk of cardiovascular events." They go on to note that other genetic studies have led to similar conclusions about CRP but also that the hypothesis remains to be demonstrated in a randomized trial.

And, Schunkert and Samani write, the current study of people with genetically elevated CRP doesn't contradict the idea that inflammation, which elevates CRP, also contributes to vascular disease. "Moreover, the study does not diminish the validity of CRP as a risk marker of atherosclerotic disease."

Commenting to heartwire , Dr Eric J Topol (Scripps Translational Science Institute, La Jolla, CA), an expert on the genetic basis of heart disease, said that the study from Zacho et al "certainly does not support CRP as being the key player that drives [cardiovascular] outcomes and helps to provide new insights in an area that has had substantial work yet conflicting results."

Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA), who pioneered and continues to explore the role of CRP as a marker and potential mediator of cardiovascular risk, told heartwire that the current findings "reconfirm that individuals with elevated high-sensitivity [hs] CRP are at high risk for heart attack and stroke, even when LDL is low.

"Whether CRP is more than a biomarker and actually causal for cardiovascular disease is simply unknown and requires direct clinical experimentation," Ridker said. "Since the genetics of CRP are complex and involve no fewer than seven distinct loci, it is not at all surprising that a study limited to just a few single-nucleotide polymorphisms would yield a null result."

The analysis combined 10 276 persons randomly selected from the community for the Copenhagen City Heart Study, 31 992 from the cross-sectional Copenhagen General Population Study, 2238 patients with ischemic heart disease in the Copenhagen Ischemic Heart Disease Study, and 612 with ischemic cerebrovascular disease in the Copenhagen Carotid Stroke Study; none of the participants in the overall analysis were from more than one of the contributing studies.

The hazard ratio (HR) for ischemic heart disease (including fatal or nonfatal MI, symptomatic myocardial ischemia, and revascularization) in persons with hs-CRP >3 mg/L vs those with levels <1 mg/L was 1.6 (95% CI 1.2–2.1) and for ischemic cerebrovascular disease was 1.3 (95% CI 0.8-2.0) after adjustment for factors known to influence CRP, including age, sex, lipoprotein fractions, body-mass index, antihypertensive therapy, dyslipidemia therapy, hormone-replacement therapy, menopausal status, diabetes, smoking, and alcohol intake. For both end points, the trend of a rising HR with increasing CRP-concentration tertiles was significant at p<0.001.

An analysis of different genotype combinations for the four CRP-associated polymorphisms showed rises in associated plasma-CRP levels of up to 64%; the variation in CRP levels by genotype combination was significant at p<0.001.

The group then estimated how risk might be associated with the genetically elevated CRP levels based on corresponding determinations of CRP-related risk in the general population, if CRP were indeed to be a cause of vascular disease.

"On the basis of this assumption, we estimated that the 64% increment in plasma CRP levels due to CRP-genotype combination would predict increased risks of up to 32% (HR 1.32, 95% CI 1.26- 1.39) for ischemic heart disease and of up to 25% (HR 1.25, 95% CI 1.15-1.35) for ischemic cerebrovascular disease."

However, no such significantly increased risk by CRP-genotype combination was actually observed for either end point in any of the four cohorts, suggesting that CRP elevations weren't contributing to ischemic vascular disease in these populations, according to the researchers and editorialists.

While that may undermine hopes for CRP as a treatment target in patients with vascular disease, Ridker points out that "whether or not hs-CRP can be used to identify high-risk populations who might benefit from statin therapy is a core issue in the JUPITER trial." Ridker chairs the international randomized, controlled trial with >17 000 patients and is scheduled to present it at the American Heart Association 2009 Scientific Sessions on November 9.

JUPITER randomized patients without a history of MI, revascularization, stroke, or diabetes and with LDL-cholesterol levels <130 mg/dL but hs-CRP of at least 2 mg/dL to receive rosuvastatin (Crestor, AstraZeneca) at 20 mg/day or placebo.

On March 31, 2008, as reported then by heartwire , AstraZeneca announced that it was stopping the trial early after the emergence of "unequivocal evidence of a reduction in cardiovascular morbidity and mortality" among patients who received the active drug [3].

The study was supported by the Danish Heart Foundation. Of the coauthors, Dr Børge G Nordestgaard (Herlev Hospital) reports consulting fees from BG Medicine and AstraZeneca and lecture fees from AstraZeneca, Sanofi-Aventis, Merck, Pfizer, and Boehringer Ingelheim; Dr Henrik Sillesen (Rigshospitalet, Copenhagen, Denmark) reports consulting fees from Merck, Pfizer, BG Medicine, Boehringer Ingelheim, Sanofi-Aventis, and AstraZeneca; Dr Peer Grande (Rigshospitalet) reports consulting fees from AstraZeneca; and Dr Anne Tybjærg-Hansen (Herlev Hospital) reports lecture fees from Pfizer and Sanofi-Aventis. Topol is editor-in-chief of Ridker has disclosed receiving grants from AstraZeneca, Sanofi-Aventis, and Novartis; consulting for AstraZeneca, Novartis, Dade, Merck, Schering-Plough, Roche, and Abbott; and being listed as a coinventor on patents that relate to the use of inflammatory biomarkers in cardiovascular diseases.

  1. Zacho J, Tybjærg-Hansen A, Jensen JS, et al. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 2008; 359:1897-1908. x1953

  2. Schunkert H, Samani NJ. Elevated C-reactive protein in atherosclerosis — chicken or egg? N Engl J Med 2008; 359:1953-1955.

  3. AstraZeneca. Crestor outcomes studyJUPITER closes early due to unequivocal evidence of benefit [press release]. March 31, 2008. Available at:

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