A protein used by doctors to indicate a patient's risk of coronary heart disease may have drug developers barking up the wrong treatment tree, according to the authors of a study published in the Journal of the American Medical Association (JAMA). Their research suggests that C-reactive protein, an enticing target for scientists working on new treatments for coronary heart disease, may not have a role in causing the disease, even though it is a predictive marker.
Coronary heart disease is the leading cause of death worldwide and is particularly common in Western countries, including the UK, where it is responsible for over 100,000 deaths per year. It is caused by atherosclerosis, where plaques and fatty acids build up in the walls of the arteries.
The progression of the disease from early to later, sometimes fatal, stages involves inflammation. There is strong interest in measuring levels of C-reactive protein in a patient's blood, because it is a marker of inflammation.
Previously, scientists had not known whether C-reactive protein causes coronary heart disease, even though a number of studies over the past 12 years have indicated that it is a risk indicator.
Today's study, by researchers from Imperial College London and 12 other universities and institutes in Europe and North America, looks at the genes that control C-reactive protein levels in blood and their effect on the risk of coronary heart disease. Variations in the gene that codes for C-reactive protein were not associated with risk of coronary heart disease, which the authors say argues against C-reactive protein being directly involved in causing the disease. However, interest still remains in whether C-reactive protein is a useful marker of disease risk.
In the same study, the authors identified genetic variations in three other genes associated with C-reactive protein, which according to the authors, may also be associated with a person's risk of coronary heart disease.
Professor Paul Elliott, lead author of the paper, from the Department of Epidemiology and Public Health at Imperial College London, said: "Coronary heart disease is a common cause of death, especially in the UK and other western countries, and scientists have been looking for new ways to treat the disease and reduce mortality. Some researchers thought C-reactive protein would be a good molecule to target, as raised levels of this protein in the blood are associated with increased risk of coronary heart disease. However our research suggests that the association may not be causal, so attempts to target this protein to reduce the risk of the disease are unlikely to be fruitful."
"We have also discovered new genetic variations that are associated with coronary heart disease. If confirmed in other studies, these might give clues to identify new targets to treat the disease," added Professor Elliott.
The researchers identified 160 genetic variations in 5 genetic regions associated with C-reactive protein levels by carrying out a Genome-Wide Association Study involving 17,967 people.
Two of the genetic regions identified in this study have not previously been associated with risk of coronary heart disease. These genes code for receptors involved in regulating appetite and weight, and inflammation. Further research is needed to confirm whether they also confer susceptibility to coronary heart disease.
The results of further studies showed that there was no significant difference in the frequency of variations in the gene that codes for C-reactive protein between people with and without the disease. This suggests that C-reactive protein does not cause coronary heart disease.
The researchers reached their conclusions by comparing data from different studies showing the association between these genetic variations and coronary heart disease. They looked at a total of 28,112 people with the disease and 100,823 people without the disease.
- Paul Elliott; John C. Chambers; Weihua Zhang; Robert Clarke; Jemma C. Hopewell; John F. Peden; Jeanette Erdmann; Peter Braund; James C. Engert; Derrick Bennett; Lachlan Coin; Deborah Ashby; Ioanna Tzoulaki; Ian J. Brown; Shahrul Mt-Isa; Mark I. McCarthy; Leena Peltonen; Nelson B. Freimer; Martin Farrall; Aimo Ruokonen; Anders Hamsten; Noha Lim; Philippe Froguel; Dawn M. Waterworth; Peter Vollenweider; Gerard Waeber; Marjo-Riitta Jarvelin; Vincent Mooser; James Scott; Alistair S. Hall; Heribert Schunkert; Sonia S. Anand; Rory Collins; Nilesh J. Samani; Hugh Watkins; Jaspal S. Kooner. Genetic Loci Associated With C-Reactive Protein Levels and Risk of Coronary Heart Disease. JAMA, 2009; 302 (1): 37-48 [link]
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