Genetic link suggested in deaths from cardiac valve diseases

Nov 2 2004

Deaths from cardiac valve diseases appear to run in families, suggesting a significant genetic component, according to a study published in Circulation: Journal of the American Heart Association.

“These findings suggest that unknown genetic factors contribute to death due to mitral valve disease and death due to non-rheumatic aortic valve disease,” said Benjamin Horne, lead author of the study and a Ph.D. candidate in genetic epidemiology at the University of Utah’s department of medical informatics in Salt Lake City. “Future studies will attempt to discover the genes responsible for such risk.”

The mitral valve is located between the heart’s left atrium and left ventricle. The aortic valve is between the left ventricle and the aorta. Non-rheumatic refers to not being caused by rheumatic fever.

Using death certificates and genealogy data from the Utah Population Database, researchers studied people who died of aortic and mitral valve disease. The broad database makes the study unique, researchers said.

“While some small studies have suggested that some types of mitral valve disease may aggregate in families, this study used a population database that included millions of individuals across several centuries with their genealogical relationships to each other and with 250,000 death certificates for those from the 20th century,” said Horne, who also works in the cardiovascular department at LDS Hospital in Salt Lake City.

The familial clustering observed was especially strong among those who died of non-rhuematic mitral valve disease, with first-degree relatives of a person with mitral valve disease being more than two-and-a-half times more likely to die of mitral valve disease. The second-degree relatives of those who died of mitral valve disease also were 67 percent more likely to die of the disease, despite only sharing half as much DNA as do first-degree relatives.

In the study, analysis of non-rhuematic fever related deaths showed that 932 deaths were due to aortic valve disease, 1,165 to mitral valve deaths, and 2,504 deaths to disease in any valve including the aortic and mitral valve (with the 407 additional deaths attributed to the tricuspid, pulmonary or unspecified valve, with “unspecified” composing the majority of these).

Horne said the degree to which the valve diseases appeared to aggregate in families was surprising. “It was a similar or greater degree than for other diseases such as breast cancer and prostate cancer for which major genes have been found. This suggests that it is promising that we will be able to find genes for the valve diseases.”

Another 4,713 deaths related to rheumatic heart disease were also studied. Although rheumatic heart disease clustered primarily among nuclear families, suggesting a strong environmental rather than genetic effect, a small degree of aggregation occurred among more distant relatives. This may suggest that some small genetic effect influences human response to the infectious cause of rheumatic heart disease.

Average age at death from aortic valve disease was significantly older (age 78) than for mitral valve (age 62) and rheumatic heart disease (age 60). Researchers observed no differences in ages at death between males and females in any death category.

However, when looking only at deaths before age 65, the genetic link across all categories is strikingly stronger, researchers said.

“This is a characteristic often noted for diseases with a strong heritable component and suggests that genetic studies may be best served by restricting ascertainment to early-onset forms of the disease,” Horne said.

Because the study population is primarily Caucasian, the results may not allow generalization to members of other ethnic groups.

“While valvular genetic factors may directly lead to death, it may be that valve problems aggravate other diseases that lead to death. If so, the genetic effects measured may represent the genetics of other valve-associated diseases,” Horne said.

“The next step will be to enroll families in whom these diseases appear in excess in a study to discover DNA regions that may harbor the gene or genes that predispose them or contribute to disease.”

Cardiac valvular diseases lead to more than 42,000 deaths in the United States each year.

Co-authors are Nicola J. Camp, Ph.D.; Joseph B. Muhlestein, M.D.; and Lisa A. Cannon-Albright, Ph.D.

http://www.americanheart.org