MURRAY — An international team of heart researchers including Intermountain Medical Center cardiologists have identified 13 previously unrecognized genetic markers linked to coronary artery disease. The study, hailed by researchers as a first major step toward finding new treatments, was released Sunday in the journal Nature Genetics.
Coronary artery disease (CAD), caused by plaque buildup, is the leading cause of death for both males and females. Narrowing or blockage of the arteries can cause angina or heart attack. CAD can also lead to heart failure and arrythmias.
To do it, teams of scientists across two continents in 14 different studies gathered DNA samples of more than 85,000 patients of European descent who had heart disease, then validated the findings with another 60,000, including thousands who are part of the Intermountain Heart Collaborative Study.
Along the way, the scientists also found that two genetic markers previously suspected of creating risk for CAD did not, said Dr. J. Brent Muhlestein, research cardiologist and one of the IMC team. The new research brings to 23 the number of genetic markers shown to have implications for coronary artery disease.
New technology has made it possible to test hundreds of thousands of locations in human DNA at the same time, said Benjamin Horne, Ph.D., in charge of genetic and cardiovascular epidemiology at IMC, who headed the Utah research effort. Using such a broad pool of researchers and test subjects, they were able to look at a million genetic factors.
Ten percent of the validation group, which included both those with CAD and those without, came from Intermountain's cardiovascular database. Intermountain has been recruiting heart patients to donate blood samples for its database for 18 years, said Muhlestein. After they look at a patient's arteries using angiography, he said, they ask patients if they want to help researchers study and understand heart disease. By the thousands, Utahns have willingly signed the consent forms and had blood drawn.
Intermountain, which is the only Utah facility to participate, joined the international study, called the CARDIoGRAM consortium, two years ago.
Only three of the 13 just-found genetic markers are related to traditional risk markers, Horne said, while the other 10 are "in genes we would never have guessed."
And while all 23 genetic markers are considered "significant," each plays only a "modest role" in heart disease, said Dr. Jeffrey L. Anderson, director of cardiac research at IMC's Heart Institute. Now researchers have to figure out how those markers interact. Such an understanding is expected to lead to new treatments for CAD, which is a complicated killer.
In a release accompanying the announcement, Horne used the example of a genetic marker on chromosome 9p21. Scientists say it is perhaps the most influential for coronary artery disease, but its "neighborhood" on the chromosome doesn't code for any specific gene or understood function. Scientists think it regulates other genes, but which? And how? Such understanding is key to developing treatments.
There are more than 3 billion pairs of letters in the DNA alphabet that makes up the human genetic code. The researchers studied one million genetic markers to find the new 13 involved in coronary artery disease, something they could only accomplish with a very large patient sample to "show patterns in such tiny bits of information," as the release put it.
Where processing of such a massive project used to be done by hand, there are now automated systems. Intermountain can now process up to 200 people a day, said John Carlquist, Ph.D., a microbiologist who runs the lab where the work was done at Intermountain.
Heart disease, like other ills, is "multifactorial," said Anderson, who added that there's much more to be done to understand both environmental and genetic factors of heart disease. He said 40-50 percent of the risk is genetically based. And "this massive effort in 150,000 people only explains about 20 percent of the risk." That leaves an awful lot unexplained.
Because most of the risk is not genetic, but environmental, "we need to know our numbers," such as blood pressure, he said. Among known risk factors are smoking, diabetes, high blood pressure, high cholesterol and diabetes.
The lead institution in the study is the University of Lubeck in Germany. The research subjects were from Europe, Canada and the United States.