Public Release: 

Mutation in 'elastic' gene linked to early coronary heart disease

American Heart Association

DALLAS, Aug. 6 - A mutation in a gene that affects artery elasticity is associated with an increased risk of early coronary heart disease, researchers report in today's rapid access issue of Circulation: Journal of the American Heart Association.

The Dutch study shows that a specific mutation in a gene called ABCC6 was more common in people who developed coronary artery disease before age 50 than among healthy people. The mutation is called R1141X. It can be inherited or occur spontaneously.

ABCC6 is in a family of genes called the adenosine triphosphate binding cassette genes. Genes in this family code for proteins that transport molecules into and out of cells. Researchers have not yet discovered the function of the ABCC6 gene. However, given the effects observed when this gene is mutated, they theorize that it most likely plays a role in keeping elastic fibers healthy.

The mutated ABCC6 gene causes pseudoxanthoma elasticum (PXE), a rare disorder of the connective tissue in the skin, retina and artery walls that occurs in about 1 in 100,000 people.

PXE causes the breakdown of elastic fibers and tissues become hardened with calcium. Cardiovascular signs of PXE include premature coronary artery disease caused by elastic fibers calcifying in the arteries.

The R1141X is the most frequent mutation found in the ABCC6 gene in PXE patients in The Netherlands and apparently throughout Europe.

Researchers wondered if having just one copy of the mutated gene might increase a person's chances of developing early heart disease without other symptoms of PXE.

In a study of nearly 1,500 Dutch people, they found that carriers of this mutation were 4.2 times more likely to have heart disease before age 50 than non-carriers.

"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 and an internist at the University of Amsterdam in The Netherlands. "The R1141X mutation is associated with a sharply increased risk of coronary heart disease."

In their study, Trip and her colleagues enrolled 441 patients younger than age 50 who had suffered a heart attack, undergone a procedure such as angioplasty to restore blood flow to their hearts, or whose angiograms showed a major heart artery blocked 70 percent or more.

These patients were matched with 1,057 Dutch people without heart disease. Both groups participated in a project that screened people in three Dutch cities for cardiovascular risk factors from 1987-91. 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 the exact make-up of the two copies of the ABCC6 gene in each person.

"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."

Fourteen (3.2 percent) of the 441 heart patients carried a single copy of the mutation compared to eight (0.8 percent) of the 1,057 healthy people.

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


Co-authors are Yvo M. Smulders, M.D., Ph.D.; Jurgen J. Wegman, M.D.; Xiaofeng Hu, M.D.; Jolanda M. A. Boer, Ph.D.; Jacoline B. ten Brink, Ing.; Aeilko H. Zwinderman, Ph.D.; John J. P. Kastelein, M.D., Ph.D.; Edith J. M. Feskens, Ph.D.; and Arthur A. B. Bergen, Ph.D.

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