In a serendipitous spin-off of HIV/AIDS research, scientists at the National Institute of Allergy and Infectious Diseases (NIAID) and colleagues have found strong evidence that a genetic variation affecting immune system cells protects against heart disease. Details of the work, which also provides further evidence for the role of inflammation in heart disease, will appear in the April 15 issue of the Journal of Clinical Investigation.
“This work demonstrates how NIAID’s commitment to HIV/AIDS research can provide insights into the mechanisms of other diseases,” says NIAID director Anthony S. Fauci, M.D. “The money spent on this research, so important to the millions of people around the world infected with HIV, also results in wider ranging benefits.”
“The genetic variation we studied has a positive and protective effect against atherosclerosis. This effect is similar in magnitude, though opposite in value, to known negative risk factors such as diabetes and smoking. In other words, as bad as the negative risk factors are bad, this factor is good,” says senior study author Philip M. Murphy, M.D. “In addition, the study may help explain part of the hereditary component of heart disease, establishing not only a genetic association but also giving evidence for a biological cause.”
Dr. Murphy and colleague David McDermott, M.D., have been studying several different receptor molecules on the surface of immune system cells to understand the role these molecules play in HIV infection. Recently, they concentrated on a receptor molecule called CX3CR1, which binds to a signaling molecule called fractalkine. Fractalkine, sometimes found in atherosclerotic vessels, attracts immune system cells bearing CX3CR1 and helps them attach to infected or diseased tissue. The NIAID scientists speculated that in atherosclerotic tissues, fractalkine might attract immune system cells and encourage them to bind to the walls of blood vessels, thereby triggering inflammation and plaque formation that eventually blocks the vessel.
Working with colleagues at the National Heart, Lung, and Blood Institute (NHLBI), the NIAID scientists performed a detailed genetic analysis of the offspring cohort of the famous Framingham Heart Study. In this population of more than 1,800 individuals, the researchers showed that a genetic variant of the CX3CR1 receptor, called CX3CR1-M280, was associated with a significantly lower risk of heart disease, even after adjusting for age, sex and negative risk factors such as cigarette smoking, high cholesterol, diabetes and hypertension.
Because previous studies established that mice lacking the CX3CR1 receptor also had reduced risk of heart disease, the NIAID scientists speculated that the human CX3CR1 variant might not function well. A battery of laboratory tests proved that this was in fact the case: When compared with “normal” CX3CR1, the M280 variant did not bind well to fractalkine or respond to its attracting signal. The finding suggests that people with the M280 variation are less susceptible to arterial inflammation triggered by immune system cells. So far, there is no evidence that the variant causes any ill effects. Duke University Medical Center researcher Dhavalkumar D. Patel, M.D., Ph.D., collaborated with the NIAID team on this part of the study.
“The strength of this study is that it examined an entire population, not just one group of people already at risk for heart disease,” explains Dr. McDermott. “When you examine an entire population, you are less likely to overestimate the significance of the risk factor you are studying.” The collaboration of Dr. Christopher O’Donnell and colleagues at NHLBI and the Framingham Heart Study were invaluable to this effort, Dr. McDermott notes.
“This study provides a great example of how the Framingham genetic database can contribute to multidisciplinary collaboration,” says NHLBI Director Claude Lenfant, M.D. “This database is available for use by researchers and provides important and novel information that may one day translate to patient care.”
By establishing a connection between a specific cell receptor, CX3CR1, and atherosclerosis, the researchers have spotlighted CX3CR1 as a potential target for drugs that block its action. “Even though scientists have the entire sequenced human genome to examine, it is still extremely difficult to find drug targets unless you have robust cohorts like this one to test,” notes Dr. Murphy.
The M280 variant gene differs from the usual CX3CR1 gene at two key points. Next, the NIAID researchers would like to discover if one, the other, or both of these changes cause the variant molecule to function differently. In addition, the researchers would like to follow up on studies in mice that suggest CX3CR1 plays a role in other inflammatory diseases such as stroke or the kidney disease glomerulonephritis.
NIAID is a component of the National Institutes of Health (NIH), an agency of the Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies. Reference: D McDermott et al. Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in man. Journal of Clinical Investigation 111(8):1241-50 (2003).