Unplugged? C-reactive protein, a new study argues, does not have a hand in plaque buildup in arteries like this one.

Study Clears Protein Long a Suspect in Artery Damage

Measured by a simple blood test, c-reactive protein (CRP) has vexed scientists for years. People with elevated CRP levels tend to be at higher risk of a heart attack, but does that mean the protein is causing arteries to clog and these people require medication? A study of nearly 51,000 people in Denmark says no.

Although the study is far from the last word, researchers say it will likely shift the debate about how to use CRP in guiding treatment. The work also underscores a relatively new way to uncover a single factor's influence on disease: by isolating it genetically in a large population.

CRP was discovered in 1929. Produced by the liver, it indicates inflammation in the body. For example, CRP levels surge following a trauma to tissues. People with elevated CRP levels have a higher risk of heart attack, which is caused when plaques in arteries around the heart rupture. These plaques are the hallmarks of atherosclerosis, a disease thought to be exacerbated by inflammation. People with high CRP levels are also more likely to suffer from other health problems, such as obesity and type 2 diabetes.

But no one has pinned down whether CRP is driving disease or is merely a sign of it. The distinction is crucial for understanding how atherosclerosis develops as well as determining whether CRP is a useful drug target--and whether lowering it can save lives.

To find out whether CRP promotes vascular disease, Børge Nordestgaard, a genetic epidemiologist and physician at Copenhagen University Hospital, and colleagues analyzed DNA from 50,816 participants in four large health studies. The researchers focused on four changes in the CRP gene, each of which, researchers have found, raises CRP levels. The worst combination of the four, Nordestgaard's group confirmed, boosts levels by 64%. The scientists estimated, based on earlier studies, that this group should have about a 30% higher chance of heart attacks. But there was no increased risk for them or any of the other groups carrying supposedly deleterious DNA, the team reports in the 30 October issue of the New England Journal of Medicine. The strategy is different than previous population studies of CRP, which have generally looked not at genetics but at how CRP levels correlate with heart attacks. This other approach doesn't rule out that CRP reflects existing disease or travels along with other risk factors that are the real culprits.

"Without any doubt, this tells us that CRP's not causing atherosclerosis," says Nordestgaard. He believes instead that CRP simply points to atherosclerosis that's already there.

Not everyone agrees. Paul Ridker, a cardiologist at Brigham and Women's Hospital in Boston, is testing whether lowering CRP and cholesterol can prevent heart attacks. He wants to see "direct experimental testing" that CRP doesn't cause atherosclerosis by altering levels and then determining a person's chance of a heart attack.

But cardiologist Nilesh Samani of the University of Leicester in the U.K. says that the Danish group took "a fine approach" that can be applied to other biomarkers, especially before hundreds of millions of dollars are spent to develop drugs that target a molecule that may not in fact be causing a disease. Already, researchers have tried this genetic strategy to discern the function of high-density lipoprotein, often called "good" cholesterol, and found that it has little effect on health. Still, Samani notes that CRP can still be very useful for identifying people at high risk for heart disease, particularly those without other risk factors such as high cholesterol.

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