January 12, 2007

Elevated levels of C-reactive protein (CRP) are associated with an increased risk of cardiovascular disease (CVD) events, but whether CRP has a role in CVD pathogenesis has been the subject of much debate. In an analysis of data from the Cardiovascular Health Study, a prospective study of participants 65 years and older at baseline, CCGS/Genetics researcher Dr. Leslie Lange and colleagues identified polymorphisms (gene variants) that were associated with both increased and decreased levels of plasma CRP and risks of myocardial infarction or stroke.  This study was published in the December 13, 2006 issue of the Journal of the American Medical Association. [view JAMA article]

Several previous studies have not found any associations between CRP gene variants and cardiovascular risk, leading to conclusions that CRP may not play a causal role in heart disease. But Lange’s study, which is believed to be the first to find a genetic CRP link to cardiovascular events, is expected to lead to renewed interest in this field.

The authors analyzed data from the prospective, population-based Cardiovascular Health Study, in which 5888 men and women (aged >65 years) were followed for 13 years for the occurrence of cardiovascular events. Their results suggest that “a genetic basis may underlie, in part, the relationship between CRP concentration and cardiovascular disease risk in older adults." The direction of cardiovascular risk associated with the various genotypes tended to be consistent with associations with plasma CRP concentration measured late in life. Thus, they suggest that “C-reactive protein may be both a marker of cardiovascular disease and an active participant in the disease process. It is plausible that CRP genotype influences CRP synthesis, which in turn could mediate the onset of clinical cardiovascular events."

Lange and her collaborators concede that these data are not consistent with several other studies, pointing out that although CRP genotype was strongly associated with plasma CRP concentration, there was little association between CRP genotype and risk of MI or stroke in the Physician’s Health Study, the Framingham Heart Study, or the Rotterdam Study.  They offer a number of possible explanations for this, including the fact that their analysis included a larger sample size and larger numbers of clinical events and so had greater power to detect an association. They also note that they showed the strongest association for fatal events and suggest that CRP genotype may be more strongly associated with more severe events.