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JAMA Studies Explore Value of Cardiovascular Biomarkers

NEW YORK (GenomeWeb News) – A pair of studies in today's issue of the Journal of the American Medical Association are shedding new light on cardiovascular biomarkers and their role in predicting and influencing heart disease.

One of the studies raises questions about the added value of several cardiovascular biomarkers for determining heart disease risk compared with standard risk factors in the general population. The other provides evidence suggesting a well-known cardiovascular biomarker called C-reactive protein does not itself contribute to heart disease risk, making it questionable target for new therapeutics.

In the former study, an international research team followed a group of more than 5,000 Swedes without cardiovascular disease for about 12 years, looking at standard risk factors — such as smoking, diabetes, and high blood pressure — as well as six biomarkers. They found that several biomarkers could predict cardiovascular and coronary events on their own. But overall, the biomarkers only slightly improved their ability to predict such events when integrated into models including standard risk factors.

"Overall, the improvement in prediction risk [using biomarkers] wasn't large," senior author Thomas Wang, a researcher affiliated with Harvard Medical School and the Massachusetts General Hospital's Heart Center, told GenomeWeb Daily News. Even so, he added, there are situations in which biomarkers could be helpful — for instance, classifying individuals considered at intermediate risk based on standard risk factors.

The work was done as part of an ongoing epidemiological study in Sweden, Wang explained. Researchers followed 5,067 individuals cardiovascular heart disease from Malmö, Sweden for 12 to 15 years, assessing clinical factors along with five biomarkers: C-reactive protein, cystatin C, lipoprotein-associated phospholipase 2, midregional proadrenomedullin, midregional proatrial natriuretic peptide, and N-terminal pro-B-type natriuretic peptide.

The team kept tabs of hospitalizations and deaths in the group through the Sweden's national healthcare system and tracked cardiovascular events using Malmö's stroke registry.

The researchers reported that integrating information on one or several biomarkers only slightly improved risk prediction compared to standard risk factors alone. Adding in biomarker information reclassified just eight percent of participants with respect to cardiovascular risk and five percent with respect to coronary risk. And many of these individuals moved from the intermediate- to the low-risk group based on biomarker information.

Based on these results, Wang said, there's not much evidence supporting the use of biomarkers for screening the general population. But, he added, it's possible that these and other biomarkers could benefit sub-groups within the population.

Wang also emphasized the need to find additional cardiovascular biomarkers. Although he said biomarkers probably will not be routinely used in the immediate future, Wang predicted that they will come into their own over the next five or more years.

"Studies focusing on high-risk populations often yield favorable estimates of biomarker performance," Wang and his team wrote, "but the greatest need for new risk markers exists in low-to-intermediate-risk populations, for whom the data are most conflicting."

Meanwhile, another paper in JAMA today suggests one of these biomarkers — CRP — does not itself contribute to coronary heart disease risk. In that study, an international research team used a so-called Mendelian randomization approach to determine biomarker biology using genetics.

"[W]e were able to investigate whether the identified genetic variant in the CRP locus, together with data from other studies, were associated with coronary heart disease," lead author Paul Elliot, an epidemiology and public health researcher at the Imperial College London, told GenomeWeb Daily News in an e-mail. "In fact there was no association, arguing against a causal role for CRP in atherosclerosis."

The researchers used Affymetrix 500K mapping arrays, Illumina 317K arrays, and custom Perlegen Sciences arrays to do a GWAS for variants associated with CRP levels in 17,967 individuals. After replicating findings from the initial GWAS in more than 13,600 individuals, the researchers tested whether the most significant CRP variants also associated with coronary heart disease in published studies involving some 28,000 cases and nearly 101,000 controls.

The team uncovered five loci that with strong links to CRP levels. But they did not find an association between genetic variants in the CRP gene and coronary heart disease, suggesting CRP levels may fluctuate as a consequence of other heart disease risk factors rather than having a causal role in the these events.

Consequently, Elliott and his colleagues argued that the "development of the therapeutic strategies targeting specific reductions in plasma levels of CRP are unlikely to be fruitful."

In an editorial appearing in the same issue of JAMA, Svati Shah and James de Lemos, cardiology researchers at Duke University and the University of Texas Southwestern Medical Center, respectively, discussed the findings and implications of both studies.

Shah told GenomeWeb Daily News that the Mendelian randomization approach used by Elliott and his team is "a really interesting and exciting way to integrate biomarkers with genetics."

Even so, the duo cautioned, "the study does not negate the role of inflammation as causal in [coronary heart disease], nor does it exclude a potential biological interaction between drugs acting on other inflammatory pathways and CRP levels." As such, they argued, "[i]f CRP increases in response to other inflammatory triggers, it may still be a useful tool for personalizing selection of anti-inflammatory therapies, including statins."

Like Wang, Shah expects to see a lot of growth in the biomarker field in the next few years — not only for predicting disease risk and determining which patients should get particular treatments and diagnostic tests, but also for learning more about the biology underlying heart disease and other conditions. "The technology has exploded on the –omics side," Shah said. "We're going to be bombarded [with biomarkers] in the next few years."

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