New Heart Disease Markers Discovered
THURSDAY April 24, 2008 -- High levels of C-reactive protein, an inflammatory marker that may warn of impending heart disease, are tied to variations in genes that control metabolism, two new studies show.
The studies identify "new genes that are of potential importance for either the treatment of cardiovascular disease or potentially screening individuals who may be at higher risk of developing cardiovascular disease," said Dr. Alexander Reiner, of the University of Washington, Seattle, who authored one of the reports.
Still unresolved, however, is the exact nature of the relationship between C-reactive protein (CRP) levels and cardiovascular disease.
"That's an absolutely crucial piece of evidence that we don't have, and until we have it, we cannot know whether any of these new [genetic variants] will predict disease," said Dr. James Scott of Imperial College London, who was not involved in either study.
The reports are published in the May issue of The American Journal of Human Genetics.
Researchers have known for some time that blood CRP levels can predict one's risk of heart disease and stroke. Like the swelling that occurs when someone cuts a finger, cardiovascular disease is, to a large extent, an inflammatory condition. CRP is an indicator of that inflammation. Not surprisingly, environmental risk factors such as smoking, diet and exercise strongly influence CRP levels. But genetics also play a role -- accounting for about 40 percent elevated CRP levels, Reiner said.
"The genetic side of this is rather straightforward," explained Dr. Paul Ridker of Harvard Medical School and Brigham and Women's Hospital in Boston, who led the second study. "If we know people with high CRP levels are at risk, what governs CRP levels? There's a high environmental risk -- people who don't exercise, who smoke, who are overweight, tend to have higher CRP levels than thin, athletic people. But some thin, athletic people have high CRP levels anyway."
Some genetic factors (including variants in the CRP gene itself) had already been identified. But they accounted for only a small percentage of the variance in these levels; researchers wanted to find the other players. In separate efforts, Reiner and Ridker led research teams to see if they could locate them.
Using genetic material and data stemming from three separate cardiovascular studies that comprised more than 12,000 individuals, the groups scanned for genetic differences that correlated with elevated CRP levels. Their tools were DNA microarrays -- glass slides, about the length and width of a stick of gum, which can probe more than 300,000 individual genetic variants per individual. Reiner's team also employed a candidate gene approach, looking specifically at polymorphisms in specific genes the scientists thought might play a role.
The teams found seven genomic regions that appeared to be strongly correlated with CRP levels. Six of those regions contained genes associated in one way or another with metabolic syndrome; the seventh contained no known genes. These six genomic locations read like a Who's Who of cardiovascular disease and metabolic disorder, genes such as HNF1A, which regulates the CRP gene; the leptin receptor, which regulates weight; a regulator of glucose metabolism; and apolipoprotein E.
"I think it's quite interesting that genes involved with traits of metabolic syndrome are also associated with CRP," said Dr. Caroline Fox, medical officer of the National Heart, Lung, and Blood Institute. "I think that's the most fascinating aspect of this paper."
"From our perspective, it's an incredibly satisfying finding," said Ridker. "Often when you do genome-wide association studies, you get genes that you don't understand. In this case, we found a gene cluster that makes perfect sense."
Scott, who has performed similar (albeit unpublished) analyses, said he believed the findings. "We basically replicate all of those loci, the headline loci anyways," he said. "I'm sure it's right, absolutely."
According to Ridker, "The 'Aha' moment was recognizing that these six or seven genes are all interrelated to these metabolic pathways. The question is, I know CRP predicts heart attack and stroke, and these genes are related to CRP. Do these provide clues to what the proper interventions might be? And we think the answer is yes."
Indeed, given the link between CRP and cardiovascular disease, researchers have instigated clinical trials to determine whether individuals with elevated CRP levels, but low cholesterol, should be treated proactively. Ridker heads one of those trials, called JUPITER, which involves the use of a cholesterol-lowering statin called Crestor. On March 31, AstraZeneca announced it was closing JUPITER, "because there is unequivocal evidence of a reduction in cardiovascular morbidity and mortality amongst patients who received CRESTOR when compared to placebo."
But Scott cautioned that fundamental questions must be addressed before any drugs or therapies targeting the loci identified in these two studies can be developed.
"Is it [CRP] merely a response to inflammation, or does it make the inflammation worse?" he asked. "Until that question is addressed, these genes are not a valid drug target."
Metabolic syndrome comprises a collection of risk factors that often lead to cardiovascular disease, including abdominal obesity, elevated blood sugar, elevated blood pressure and abnormal lipids, said Fox. According to the American Heart Association, the syndrome affects almost 50 million Americans.
For more on metabolic syndrome, visit the American Heart Association.
Posted: April 2008