Yale scientists led by cardiologist Arya Mani, M.D., have identified a rare defect in a single gene associated with early heart disease and metabolic syndrome, a cluster of risk factors that includes high levels of harmful LDL cholesterol and triglycerides, low HDL, or “good,” cholesterol, hypertension and diabetes.
“The belief is that coronary artery disease and most other diseases are caused by mutations in several genes. Each gene, in combination with environmental factors, exerts a small effect, so it is very difficult to identify them in the general population,” says Mani, assistant professor of medicine. “But if we find families in which some members have an extreme form of the disease, such as very early onset, while other family members are unaffected, they are optimal for genetic research.”
As reported in the March 2 issue of the journal Science, on a research trip to his native Iran, Mani discovered one such extreme case: a man with high blood pressure, high cholesterol and diabetes who had suffered a heart attack at age 48. Although the man had been treated with coronary artery bypass surgery, atherosclerotic plaque continued to build up in his grafted heart arteries and in his carotid arteries, and he eventually died of a stroke.
When Mani looked at the medical records of 58 of this man’s blood relatives, he found that 28 had been diagnosed with early CAD—before the age of 50 in men and 55 in women—and that 23 of those 28 died at young ages; family members without CAD died much older. Test results from the 13 available family members with early CAD showed that nearly all of them had high LDL cholesterol and triglyceride levels, high blood pressure and diabetes, meeting National Institutes of Health criteria for metabolic syndrome.
With evidence of a strong genetic component in this family’s metabolic syndrome and early CAD, Mani obtained blood samples from affected and unaffected family members and returned to the School of Medicine to complete genomic analyses. Working in collaboration with Richard P. Lifton, M.D., Ph.D., chair and Sterling Professor of Genetics, Mani eventually zeroed in on a mutation that affected family members had in a gene on chromosome 12 known as LRP6.
One change in an amino acid in the LRP6 gene altered the activity of the protein it encodes, which acts in the Wnt (pronounced “wint”) signaling pathway, a network of proteins involved in normal development and in certain malignant tumors.
The family studied by Mani exhibits an extreme case of heart disease and associated metabolic Arya Mani risk factors, and the mutation he identified is quite rare. However, genes with similar functions to LRP6 and the Wnt pathway itself have been highly conserved over evolutionary time in species as diverse as frogs and humans. This suggests that the pathway has basic physiological importance, and Mani believes that further study of Wnt-related genes will reveal that defects in the pathway are involved in more common forms of cardiovascular disease.
“The main finding is the role of Wnt signaling in the development of metabolic syndrome and CAD,” Mani says. “That is where science has to focus now to understand the basic molecular mechanism of the disease.”
Lifton agrees. “We expect that studies of the Wnt signaling pathway in patients with early CAD and metabolic syndrome will provide new insight into the basic biology of disease causation and allow new approaches to disease prevention,” he says.