One Family's Gene Defect May Help Explain Heart Disease

Finding supports the notion of a 'metabolic syndrome,' scientists say

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HealthDay Reporter

THURSDAY, March 1, 2007 (HealthDay News) -- A rare genetic mutation linked to early death in members of one Iranian family casts new light on the metabolic syndrome, a constellation of risk factors for heart disease.

Metabolic syndrome includes factors such as lower-abdomen obesity, high blood pressure, blood fat disorders such as high LDL ("bad") cholesterol, and insulin resistance or elevated blood sugar levels. Generally, someone with three or more of these factors is said to have metabolic syndrome.

The new finding strongly suggests that the metabolic syndrome does exist, said lead researcher Dr. Arya Mani, assistant professor of medicine at Yale University.

"It emphasizes the fact that the association of these conditions is not by accident," Mani said. "Many have questioned whether there is a metabolic syndrome. This shows that it can be associated with a single genetic pathway."

A deeper understanding of this genetic pathway may also shed light on the causes of metabolic syndrome in people who do not carry this rare mutation. In fact, the Yale researchers have begun a program to screen for the mutation in the general population, Mani said.

His team published the findings in the March 2 issue of Science.

The research was done in collaboration with researchers in Tehran who first identified a high incidence of death from coronary artery disease in one family. Twenty-three of 28 blood relatives of the first person identified as a carrier of the mutation died of heart disease, at an average age of only 52.

The fact that some members of the family did not have any increased coronary risk pointed to a genetic defect in those members with the syndrome. A detailed genetic analysis of affected and disease-free family members pointed to one segment of chromosome 12 as the most likely site of the abnormality.

Studies showed that a gene called LRP6, involved in the body's management of LDL cholesterol -- the "bad" kind that clogs arteries -- was located on that segment.

The Yale investigators focused on LRP6 because an earlier study, by Dr. Matthew Warman at Children's Hospital Boston, found it to also be important to bone development. Interestingly, some members of the Tehran family were also prone to hip fractures at an early age.

Sure enough, the researchers found that a mutation caused by a change in a single amino acid of the protein produced by the gene was closely related to the presence of metabolic syndrome and bone weakening in the affected members of the family.

Work by another Yale researcher, biochemist Dan Wu, showed that the mutation compromised the function of the LRP6 gene in a signaling pathway, designated "Wnt." This biochemical pathway is not only important in embryonic development but also contributes to a number of basic functions in adults.

The pathway will be another important research target, said Dr. Richard P. Lifton, a professor of genetics at Yale, in whose laboratory that work was done.

"Although it's a long way off, we might ultimately develop ways to either disrupt or increase the activity of particular components of the pathway, to prevent development of metabolic syndrome and coronary artery disease," Lifton said.

The finding also points to a possible link between coronary artery disease and osteoporosis, the bone-weakening condition, so people with both conditions might someday be tested for Wnt signaling abnormalities.

Lifton compared the discovery of the metabolic syndrome gene mutation with the earliest work done about the role of cholesterol in coronary artery disease.

"If you look back on cholesterol, the work on familial hypercholesterolemia, which affects one person in a million, taught us about the relationship between cholesterol and heart disease," he said. "Studying these extreme outliers can be useful in the same way by identifying pathways that can be manipulated to treat or prevent metabolic syndrome."

More information

There's more on the metabolic syndrome at the American Heart Association.

SOURCES: Arya Mani M.D., assistant professor, medicine and cardiology, and Richard P. Lifton, M.D., Ph.D., chairman of Genetics; Sterling professor of genetics, medicine, and molecular biophysics and biochemistry, Yale University, New Haven, Conn.; March 2, 2007, Science

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