C-Reactive Protein and Atherosclerosis: No Case for Causality

But a genetics study confirms CRP’s role as a marker for cardiovascular events.

Elevated plasma C-reactive protein levels are associated with increased risk for cardiovascular events. However, scientists debate whether elevated CRP levels are a causative factor in — or just a marker of — ischemic vascular disease.

To assess the effects of genetically determined lifelong elevated CRP levels, investigators studied more than 50,000 Danish individuals from the general population of Copenhagen, including one large prospective cohort, one large cross-sectional cohort, and two small case-control groups. The researchers measured high-sensitivity plasma CRP levels and genotyped individuals for four single nucleotide polymorphisms (SNPs) in the CRP gene and for two SNPs in the apolipoprotein E gene (positive controls). All of the genetic variants are known to affect plasma levels of their respective gene products.

The investigators found an association of ischemic heart or cerebrovascular disease with elevated CRP levels, as expected. They also confirmed that the four CRP polymorphisms were associated with increases in CRP levels by up to 64%, which would amount to an increase in predicted risk for ischemic vascular disease of up to 32% for heart disease and up to 25% for cerebrovascular disease, independent of other risk factors. However, none of the CRP genotypes was associated with an increase in risk for either heart or cerebrovascular disease. By contrast, the apolipoprotein E genotypes were associated with both elevated cholesterol levels and increased risk for ischemic heart disease.

Comment: These findings strongly suggest that genetic variants associated with lifelong elevations of CRP levels are not associated with an increase in cardiovascular risk. Thus, increased CRP levels appear to be simply a marker for atherosclerosis or cardiovascular events, and future drugs targeting CRP are unlikely to provide any preventive benefit.

— Beat J. Meyer, MD

Published in Journal Watch Cardiology October 29, 2008

Citation(s):

Zacho J et al. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 2008 Oct 30; 359:1897.

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