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Heart Disease, Osteoporosis: Gene Clues

Studies Suggest Possible Genetic Markers for Cardiovascular Disease and Osteoporosis

By Todd Zwillich
WebMD Health News

Reviewed by Louise Chang, MD

March 19, 2008 -- A pair of new studies is pointing to possible genetic markers for cardiovascular disease and osteoporosis, both affecting millions of people.

The findings could give doctors new targets for preventing or treating the diseases.

Variations in one gene, called PON1, may be responsible for more than one in fifty deaths from cardiovascular events like heart attack and stroke, according to a study in The Journal of the American Medical Association.

The gene is believed to be linked to the anti-inflammatory and antioxidant properties of high-density lipoprotein, the so-called "good cholesterol" or HDL. High levels of HDL are protective against heart disease. The study suggests that genetic variations that influence PON1's effect on HDL could have a big impact on heart risk.

Searching for Genetic Clues

Researchers followed about 1,400 adult patients with a variety of risk factors for heart attack and stroke. The patients also had genetic tests for PON1 mutations.

They found that the 25% of adults with the lowest level of a measure of PON1 activity had over two times the risk of dying during the study as the 25% of adults with the highest level of PON1 activity. The risk of nonfatal heart attack or stroke between the groups was nearly four-and-a-half times greater.

Patients carrying a particular genetic variation of PON1 had double the risk of dying during the study. The mutation is called "QQ" and it was common among the study participants.

Heart disease is caused by a wide and complicated range of genetic, environmental, and behavioral factors, says Stanley L. Hazen, MD, PhD, director of cardiovascular diagnostics at the Cleveland Clinic Foundations and a study researcher. But when controlling for them, QQ192 stands out as a culprit in as many as 2.2% of all deaths from cardiovascular disease, says Hazen.

"In one out of 50 people this seems to be the root gene, or mutation, that can account for that," he says.

The results suggest that knowing one's PON1 status could give an early warning about the need for prevention strategies like eating right and regular exercise.

It could also provide a treatment target, one day letting doctors use drugs to go after slowed-down HDL machinery in patients with PON1 mutations. But don't run out and ask your doctor for a PON1 mutation test just yet, Hazen says. "The test is not available for clinical practice at this time."

Osteoporosis and Genetic Mutations

Another study points to common mutations on a gene called LRP5 as a major factor in the low bone density of osteoporosis. But the mutation may not be as big a factor in the risk of bone fractures overall, the main health risk from osteoporosis.

European researchers singled out a gene called LRP5 in a newly-published study of 37,500 patients. They found that mutations on the gene are associated with decreased bone mineral density in the spine and upper thigh bone. The study is part of an ongoing osteoporosis study funded by the European Union in nine countries.

"There is almost no uncertainty in this conclusion," says Joyce von Muers, a researcher at Erasmus Medical Center in Rotterdam, the Netherlands.

But LRP5's influence on risk for all bone fractures was less certain. Variations of the gene changed the risk of fractures "only a little," she told reporters.

The chemical pathways where LRP5 operates are already being studied as potential targets for drugs or genetic testing. But the same pathways also operate in cardiovascular disease and some cancers, meaning that any LRP5-based osteoporosis drug could wind up having undesirable side effects.

"You have to be very careful [when you] target these systems," von Muers said.

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