A prudent driver checks his tires with a pressure gauge so they're inflated to a safe level. And a careful person - or his physician - measures his cholesterol level to ward off atherosclerosis.

An over-inflated tire is easily bled of excess air, or replaced if its tread is worn. Excess cholesterol calls for medication and/or altered life style to reduce the risk of cardiovascular disease (CVD).

"We know a lot of highly characterized heart disease risk factor, such as raised lipid levels, elevated cholesterol and so on," observed immunologist/geneticist Gordon Duff at the University of Sheffield in the UK. "Obesity, diabetes and cigarette smoking are all CVD risk factors. But it's true, oddly, that half the people who experience their first heart attack do not seem to have any of these known risk factors. One explanation," he conjectured, "would be inherent genetic susceptibilities.

"The genetics of inflammation," Duff went on, "might be a place to look for inherited susceptibility factors to heart disease. And of course, the importance of knowing these is that we might be able to develop diagnostic tests, prognostic tests, which would enable us to categorize patients differently from how we do it now, to assess their risks perhaps more comprehensively, and understand what the best strategies would be to neutralize those risks."

Duff holds a tenured chair of molecular medicine at Sheffield, and directs the university's genomic medicine division. He is senior author of a paper in the twice-monthly journal Cytokine, dated May 17, 2002. Its title: "C-reactive protein levels are influenced by common IL-1 gene variations."

"C-reactive protein [CRP]," Duff told BioWorld Today, "is a risk factor for heart disease and related clinical events. It's made from liver cells, in response to cytokines - in particular the cytokine interleukin-6. And interleukin-1 is known to be a powerful stimulator of IL-6.

"When an individual has inflammation anywhere in the body," Duff explained, "there can be local signs - the redness, swelling and pain of inflammation in the joints of your hand, say, as in rheumatoid arthritis. But there would also be systemic - whole-body - changes that you could measure and monitor. In the blood there are several proteins, also made by liver cells, whose concentration goes up during the acute phase of inflammation. CRP turns out to be one of the best acute-phase proteins to measure, because it's highly sensitive to information. It goes up a lot and comes down again when the inflammation goes away. The fact that it goes up in inflammation and can be measured in the blood has proved to be clinically very valuable."

Meet The All-Powerful Cytokines

Duff described what triggers CRP: "The liver cells start making it when exposed to cytokines, which are circulating proteins that are messengers of inflammation. Two of the major cytokines associated with triggering CRP are IL-6 and its stimulator, IL-1. You can imagine a cascade where at the start of inflammation in the body, these early acting cytokines - IL-1, tumor necrosis factor [TNF] and IL-6 - are released. The IL-1 that's released will stimulate further production of IL-6. The IL-6 family members are probably responsible for triggering the liver cells to start making CRP, which we can measure in the blood."

Research cardiologist Peter Berger, at the Mayo Clinic in Rochester, Minn., is lead author of the Cytokine paper. Another co-author, immunologist/microbiologist Ken Kornman, is chief scientific officer at Interleukin Genetics Inc. in Waltham, Mass.

"Gordon Duff is a long-term key collaborator," Kornman told BioWorld Today. "Our company has a joint venture agreement with the University of Sheffield. In cooperation with Gordon's group we have worked for several years to identify which gene variations have leverage in regulating inflammation. And Mayo's Peter Berger provided us with the critical clinical components of cardiovascular patient acquisition and interpretation on a clinical basis."

Kornman was alluding to the large-scale cardiac patient trial launched at Sheffield a year ago. "They comprised several hundred patients," Duff recounted, "who came in to the cardiac center for angiography. The majority were referred with classical symptoms - chest pains, angina or breathlessness on exertion. A proportion needed angiography because of an abnormal heart scan. We started with 504 patients and finally genotyped and analyzed 464. All of the clinical evaluation was done at the Mayo Clinic, and the analyses between Interleukin Genetics and Mayo.

"I think the results were an encouraging link between the pathophysiology of heart disease and potential inherited susceptibilities based on the genetic control of inflammation," Duff said. "Like all results of this type, we anticipate that other people will test them, and we would like to see them confirmed independently. If we do get the confirmatory studies, we might well have another tool in our armamentarium to assess people with heart disease. I don't think we're looking at a time scale of months or one or two years. As this research develops over five or 10 years it will enable us to categorize individuals as to their risk for progression of disease, or complications.

"You have to understand the risk before you can tackle methods to reduce the risk," Duff pointed out. "What I see is essentially a form of true preventive medicine. The genotypes we studied are not mutations acquired in the lifetime of a defined individual. Rather, the polymorphisms in your DNA that you were born with you have inherited from your parents. Therefore, if they really do confer cardiac risk, that risk can be detected way before the start of disease. And in theory it gives us an opportunity to take steps to prevent disease happening in the first place."

Will CRP Move In On Cholesterol Levels?

"In our analysis of susceptibility variants we took into account the influences of gender, age, smoking history and so on. Smokers had higher levels of CRP than nonsmokers, and females had higher levels than males. So we took those into account in a multivariate analysis, and even when we did that the CRP correlation with genotype at IL-1 remained significant.

"This approach has the potential for development of gene diagnostics and identification of therapeutic targets," Duff suggested. "And the potential to develop strategies for risk modification may not be based on pharmaceuticals, but might be on lifestyle, or nutraceuticals, so I think it's a fertile area for R&D. Perhaps CRP levels might be routinely monitored on a par with cholesterol," he concluded.

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