Gene Variation May Lead to Early Cardiovascular Disease
Researchers at Duke University Medical Center have identified a variation in a particular gene that increases a person's susceptibility to early coronary artery disease. For years, scientists have known that the devastating, early-onset form of the disease was inherited, but knew little about the gene or genes responsible.
Svati Shah, MD, MHS, Assistant Professor in the Duke Heart Center and the Duke Center for Human Genetics, and Elizabeth Hauser, PhD, Associate Professor in the Department of Medicine and the Center for Human Genetics, have conducted several different and collaborative approaches to the problem.
In a previous study, the researchers found evidence that a region on chromosome 7 was linked to coronary artery disease, or CAD. More recently, they focused on identifying the gene in that region that confers risk of early onset CAD and identified it as the neuropeptide Y (NPY) gene.
NPY is one of the most plentiful and important proteins in the body, and is a neurotransmitter related to the control of appetite and feeding behavior as well as control of heart rate, vasoconstriction, and coronary blood flow.
They found evidence for six related variations of the NPY gene that showed evidence of transmission from generation to generation and association across a population of early-onset CAD patients.
"We also showed a strong age effect," said Hauser, who as a grad student created a special statistical method used in the study. If you have the NPY gene variants "in one of two copies (from mother and father), then you may develop coronary disease earlier."
One thousand families were painstakingly evaluated for CAD or evidence of a true heart attack, thanks to the work of William Kraus, MD, a Professor of Medicine in the Duke Heart Center. Members of the Duke University Cardiology Consortium (DUCCS) found patients willing to be in the GENECARD study.
A nonfamilial study used a collection of samples of nearly everyone who has had an angiogram at Duke since 2001, Shah said. Kraus and Christopher Granger, MD, a Professor of Medicine in the Duke Heart Center, founded this unusually rich repository, called CATHGEN, now nearing its 10,000th subject. The nonfamilial work showed a strong relationship between the NPY gene variants associated with coronary disease, according to the study published in the Jan. 2 online edition of PLoS Genetics.
The genetic results were even stronger in patients with onset of CAD before the age of 37.
"These young patients are a vulnerable population on whom CAD has a significant long-term impact, but they are particularly hard to identify and to therefore to initiate preventive therapies for," Shah said. "These and other genetic findings may help us in the future to identify these patients prior to development of CAD or their first heart attack."
They further examined NPY levels in blood and found that among the six variants in the NPY gene, there is a single-nucleotide change of the DNA code on the NPY promoter region of the gene -- the part of the gene that turns it on and off like a thermostat. This single-letter change was associated with higher NPY levels in the blood, suggesting that this was the functional change that predisposes a person to early onset CAD.
"If you had 1 or 2 copies of this mutant version of the gene, there could be a change in NPY level. The concept is that small changes over time can promote atherosclerosis (hardening of the arteries) at a very young age," Shah said. Mouse studies subsequently confirmed that the NPY pathway promotes atherosclerosis.
Neil J. Freedman, MD, Associate Professor of Medicine in the Duke Heart Center, treated the carotid arteries of mice to make them susceptible to atherosclerosis. Then the researchers infused mice with a drug that blocks the primary receptor of the NPY protein.
After a high-fat diet for six weeks, the study mice that had received the NPY-blocking drug had very little atherosclerosis. The control mice that didn't get the drug had such marked atherosclerosis that there was almost complete obliteration of the carotid artery, Shah said. "For purposes of reporting for the paper, Neil did not give us the most striking figures, because he said no one would believe it, the differences were so remarkable." Even though there was a big difference, it is still not clear how variation in NPY leads to atherosclerosis.
The next step may be to examine the children of the people who were studied. "We have already gathered data from several of these children and we are trying hard to get funding to continue the investigation," Hauser said. Studying the heterogeneity among individuals with early-onset disease -- overweight versus normal weight families, for example -- is also important, Shah said.
Funding for the study came from American Heart Association and the National Heart, Lung and Blood Institute of the National Institutes of Health.
Other authors include Lisheng Zhang, MD, Geoffrey S. Ginsburg, MD, and Michael H. Sketch, MD, of the Duke Heart Center, Department of Medicine; David R. Crosslin, MS, Carol Haynes, AB, Jessica Johnson, BS, Sarah Nelson, BS, Jessica J. Connelly, PhD, and Simon G. Gregory, PhD, of the Duke Center for Human Genetics; David C. Crossman, MD, of the University of Sheffield School of Medicine, Sheffield, UK; Christopher J.H. Jones, MD, the Wales Heart Institute, Cardiff, U.K.; Liyong Wang, PhD, Jeffery Vance, MD, PhD, and Pascal J. Goldschmidt-Clermont, MD, of the Miller School of Medicine, University of Miami, Miami, Fla.; Michael Muehlbauer, PhD, and Christopher B. Newgard, PhD, of the Stedman Center for Nutrition and Metabolism at Duke; and David H. Stone, MD, of the Duke Department of Surgery.