NEW YORK (Reuters Health) – C-reactive protein (CRP) does not appear to have a causal role in coronary heart disease (CHD), and using it to predict the risk of cardiovascular events offers little added benefit over use of conventional risk factors, according to two studies in the July 1 issue of the Journal of the American Medical Association.

In the first study, Dr. Paul Elliott of Imperial College London, and colleagues performed a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP levels.

The analysis, Dr. Elliott and colleagues report, “confirms the associations of common genetic variants in the LEPR, IL6R, CRP, and HNF1A loci and APOE-CI-CII cluster with CRP levels.”

The team then performed a mendelian randomization study in 28,112 cases and 100,823 controls of rs7553007, the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus, and other CRP variants. None of the minor alleles of any of those variants were associated with CHD risk.

“The lack of association with CHD of genetic variants in the CRP locus,” they conclude, “suggests that the observational data linking CRP levels and CHD may be confounded by association with other CHD risk factors, or reflect a secondary inflammatory response associated with atherosclerosis (reverse causation), rather than indicate a causal relationship.”

Therefore, “development of therapeutic strategies targeting specific reductions in plasma levels of CRP are unlikely to be fruitful,” Dr. Elliott and colleagues write.

In the second study, Dr. Olle Melander from Lund University, Malmo, Sweden and colleagues evaluated several contemporary cardiovascular biomarkers, individually and in combination, for their usefulness in predicting cardiovascular events, when compared with conventional risk factors.

The study included 5,067 men and women (mean age, 58 years) free of cardiovascular disease between 1991 and 1994. Study subjects underwent measurement of older biomarkers (CRP and N-terminal pro-B-type natriuretic peptide, N-BNP) and the following newer biomarkers: cystatin C, lipoprotein-associated phospholipase-2 (Lp-PLA2), midregional proadrenomedullin (MR-proADM), and midregional proatrial natriuretic peptide (MR-proANP).

During median follow-up of 12.8 years, there were 418 cardiovascular events and 230 coronary events.

According to the investigators, “The best combinations of biomarkers were CRP and N-BNP for predicting cardiovascular events and MR-proADM and N-BNP for predicting coronary events.”

Still, “The use of multiple biomarkers minimally improved the accuracy of risk prediction models over and above conventional cardiovascular risk factors and did not reclassify a substantial proportion of individuals to higher or lower risk categories,” the investigators note.

“Our data indicate that a relatively small proportion of individuals are moved to new risk categories by the addition of biomarkers – 8% or fewer when both upward and downward risk category movement are included and fewer than 1% when only the movements likely to lead to changes in therapy according to the Adult Treatment Panel III guidelines are included.”

“Furthermore, these reclassifications result in only modest improvements in the overall concordance between risk categories and actual event rates, as measured by the net reclassification improvement,” Dr. Melander and colleagues report.

The authors of a commentary on the two studies say, “In the future, better biomarkers and more creative strategies for combining them will be needed, along with comprehensive statistical and functional evaluation of causality, to fulfill the promise of biomarkers for personalized medicine.”

Reference:
JAMA 2009;302:37-57,92-93.