Summer 2005

Researchers Probe Genetic Mechanisms of CV Disease

A patient with high triglycerides and LDL cholesterol might seem to be a good candidate for statins, which have been shown to dramatically lower the risk of a heart attack. But for 100,000 people in the United States who have high tryglyceride and LDL levels because of a deficiency in 7-alpha-hydroxylase, statins will do little good. UCSF researchers have discovered that a variant in the gene that expresses this enzyme interferes with the action of these widely prescribed drugs. The researchers have now started testing patients for the enzyme deficiency, and those who test positive are given other therapies to reduce their lipid levels.

Improving patient care by testing for 7-alpha-hydroxylase deficiency is only one of the initial fruits of an effort by UCSF researchers John Kane, M.D., PhD, and Mary Malloy, M.D., to screen the genome for key genes that affect cardiovascular health. They have already collected about 20,000 DNA specimens and have analyzed over 9,000 genes for an association with heart attack risk.

The ability to apply pharmacogenetics in the clinic, although important, is only one of the major goals of the project. The first objective is diagnostic: to be able to tell when someone who has high cholesterol, for example, may not be at high risk for a heart attack, while someone with low cholesterol may be at high risk.

The UCSF researchers have been collecting genetic samples from people with premature coronary artery disease, and have also started collecting samples from elderly people who are unusually healthy. "Just last year, we were at the Senior World Games and collected DNA specimens from 1,000 participants," Kane says. "We got a sample from a 97-year-old man who runs the 5K, and from the 104-year-old man who carried the torch in the games." The oldest person sampled is a 108-year-old woman who still drives her car to the store and back. Samples from these people offer potentially instructive opposites to those from the 35-year-olds who have triple-vessel coronary artery disease, Kane says.

As important as individual genes are in causing disease, the group is finding that the interaction of genes is even more important. The UCSF group is spearheading the effort to identify the genes whose interactions multiply risk for heart disease.

Ultimately, the combination of genetic information and clinical history may lead to previously unknown causes of atherosclerosis and other diseases. There is evidence that this is already happening. The UCSF researchers have found that one of the genes associated with higher risk for heart disease is normally involved in inflammatory reactions. "There would have been no logical pathway to some of the candidate genes," Kane says. "The only way to find some of them is to go fishing for them in vulnerable populations."

Conversely, genetic insights into atherosclerosis also might provide information about the mechanisms underlying other diseases. Kane and Malloy are collaborating with other UCSF researchers, who are interested in macular degeneration -- which has many mechanisms in common with atherosclerosis -- and with researchers interested in maturity-onset diabetes and in fatty liver disease.

The final goal is to produce a diagnostic test that would not only be predictive of cardiac disease or stroke, but also show the mechanisms involved. "I think we are now at the point in the field of human genetics that Louis Pasteur was in bacteriology," Kane says. "It's going to be a fabulous era; it will transform medicine."

To contact Dr. John Kane, call (415) 476-1517. To contact Dr. Mary Malloy, call (415) 476-2754.

Related Information

News Releases

New Director for Gladstone Institute
Deepak Srivastava, M.D., was named the new director of the Gladstone Institute of Cardiovascular Disease (GICD).

Researchers Identify Genes Linked to Lung Transplant Rejection
Researchers at the San Francisco VA Medical Center and UCSF have identified genes associated with lymphocytic bronchitis, which is thought to lead to obliterative bronchitis (OB), a common cause of long-term failure of transplanted lungs.