Chapel Hill, NC - A new study has shown associations among C-reactive protein (CRP) gene variants, plasma CRP levels, and cardiovascular risk in older adults, reigniting suggestions that CRP could play a causative role in heart disease [1].

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 the current 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 study, published in the December 13, 2006 issue of the Journal of the American Medical Association, was conducted by a group led by Dr Leslie Lange (University of North Carolina, Chapel Hill). They explain that CRP plays an important role in acute and chronic inflammation and that inflammation contributes to all phases of atherosclerosis, from fatty-streak initiation to cardiovascular events. Although some data from experimental models support a role of CRP in atherogenesis, its direct involvement remains in question.

Noting that CRP gene variants affect plasma levels of CRP, the researchers suggest that CRP alleles associated with higher CRP levels would confer an increased risk of heart disease. They also suggest that CRP gene variants may reflect lifetime exposure to CRP more accurately than CRP serum concentrations measured at a single point in time.

To investigate this further, they 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. Common carotid artery wall intima-media thickness (CIMT) was determined at the baseline examination. For this CRP study, Lange et al included only individuals who reported race as white or black and who had not had a prior MI or stroke at baseline. The researchers analyzed DNA samples and measured CRP levels in stored blood samples taken at baseline. Four tag single-nucleotide polymorphisms (SNPs) were genotyped in 3941 white participants and five tag SNPs were genotyped in 700 black participants.

During the study follow-up, there were 461 incident MIs, 491 incident strokes, and 490 cardiovascular deaths in white participants, and 67 incident MIs, 78 incident strokes, and 75 cardiovascular deaths in black participants. The researchers found two CRP gene polymorphisms—the 1919T and 790T alleles—that were associated with higher CRP levels in white and black participants, respectively. In white participants, the 1919T allele was associated with increased risk of stroke and cardiovascular mortality, and in black participants, homozygosity for the 790T allele was associated with a fourfold increased risk of MI compared with homozygosity for the 790A allele.

One allele (3872A) was associated with lower CRP levels in both populations, and another (2667C ) with lower CRP levels in white participants only, and both these alleles were associated with decreased risk of cardiovascular death in white individuals. However, there was no association between carotid artery wall intima-media thickness and any CRP gene polymorphism in either population.

Lange and colleagues say their results "suggest that a genetic basis may underlie, in part, the relationship between CRP concentration and cardiovascular disease risk in older adults." They point out that the association between CRP genotype and plasma CRP concentration confirms previous findings in younger adults and that "together these results provide strong evidence that genetic variation within the CRP gene influences plasma CRP levels over the adult life span."

Noting that the direction of cardiovascular risk associated with the various genotypes tended to be consistent with associations with plasma CRP concentration measured late in life, they say: "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."

The researchers further point out that the association between CRP genotype and clinical events, together with the absence of association between CRP genotype and carotid artery wall intima-media thickness, suggests a greater involvement of CRP in the transition from subclinical to clinical disease than in atherosclerosis progression.

"C-reactive protein is present in atherosclerotic plaques and has been associated both experimentally and clinically with plaque instability and thrombosis, which might increase the propensity toward acute ischemic events, such as MI or stroke," they comment. They also suggest other mechanisms—such as CRP causing a procoagulant phenotype through induction of tissue factor and plasminogen activator inhibitor 1 expression in vascular cells or blood monocytes, or its complement dependent ability to enhance ischemia-induced myocardial tissue damage and cerebral infarct size.

The authors 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 greater 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.

In addition, the participants in the Physician's Health Study were younger, and it may be that older persons have had greater exposure to environmental triggers, thus allowing genetic susceptibilities to become more evident, they suggest. "Therefore, confirmation of our findings in other large population studies of older adults with large numbers of fatal events will be important for clarifying the role of the CRP gene and risk of cardiovascular disease," they conclude.

Commenting on the study for heartwire, Dr Aroon Hingorani (University College London, UK), who is also working in this field, said: "This large and well-conducted study emphasizes the consistent pattern emerging on the influence of CRP gene variants on CRP plasma levels. This gives us the opportunity to use these gene variants to study the causal role of CRP in heart disease. Additional large-scale analyses in this area would now be welcome."