A mutation in a gene that affects arterial elasticity is associated with an increased risk of early coronary heart disease, according to an article in the August 6th rapid access issue of Circulation. The Dutch study shows that a specific mutation in the gene called ABCC6 was more common in people who developed coronary artery disease before age 50 years than among healthy people. The mutation itself is termed R1141X.

ABCC6 is a member of the gene family called the adenosine triphosphate binding cassette genes, which encode proteins that transport molecules into and out of cells. Researchers have not yet discovered the function of the specific gene. However, based on the loss of elasticity associated with the mutation, they theorize that it probably plays a role in keeping elastic fibers healthy.

The mutation causes pseudoxanthoma elasticum, a rare disorder of connective tissue in the skin, retina, and arterial walls characterized by breakdown of elastic fibers and calcification of tissues. Cardiovascular signs include premature coronary artery disease caused by calcification of arterial elastic fibers.

The specific mutation identified by the researchers is the most frequent mutation found in the ABCC6 gene in patients with pseudoxanthoma elasticum in The Netherlands and apparently throughout Europe.

Researchers wondered if heterozygous carriers might have an increased risk of developing early heart disease. In a study of nearly 1,500 Dutch adults, they found that carriers of the mutation were 4.2 times more likely to have heart disease before age 50 years than individuals homozygous for the normal gene form.

"Our results seem to indicate that the R1141X mutation in the ABCC6 gene is not rare in the general population and contributes to an increased propensity toward premature heart disease," says Mieke D. Trip, M.D., the report's lead author. "The R1141X mutation is associated with a sharply increased risk of coronary heart disease."

In their study, Trip and colleagues enrolled 441 patients younger than age 50 years who had suffered a myocardial infarction, undergone a reperfusion procedure such as angioplasty, or whose angiograms showed blockage of 70 percent or more in a major coronary artery.

These patients were matched with 1,057 Dutch adults without heart disease. Both groups participated in a project that screened people in three Dutch cities for cardiovascular risk factors. All of them agreed to allow their frozen blood samples to be used in future research studies. Researchers extracted DNA from the blood sample of each member of the two groups, and identified each individual's genotype.

"We demonstrated that a strong association exists between the R1141X mutation in the ABCC6 gene and the presence of premature coronary artery disease," Trip says. "In addition, we could not find a relationship between this mutation and other major risk factors for heart disease, suggesting that this mutation is operating through a novel pathway to cause coronary heart disease."

The prevalence of heterozygous individuals was 3.2 percent (14 of 441) among heart patients compared with 0.8 percent (8 of 1,057) among healthy adults.

"If our data are confirmed in other studies, this might have implications for genetic screening in pseudoxanthoma elasticum families and may require a more aggressive approach toward coronary heart disease prevention in these individuals," Trip says.