Gene Variant Linked to Heart Disease

Two competing teams of researchers have identified the same genetic variant, located on human chromosome 9, that confers a 40 to 60 percent increased risk of heart disease in the studied populations.

Heart disease is the leading cause of death worldwide. “Because it is such a common disease, people were concerned it would be difficult to find genetic variants that predispose to it, but now we have it,” says Kari Stefansson, one of the team leaders and the CEO of Iceland’s DeCode Genetics, which has been a key player in the quest to identify disease genes. The DeCode scientists, says Stefansson, found a genetic variant that predisposes people to “early-onset heart attack in males under 50 and women under 60.”

The roots of heart disease are complicated because there are both genetic and environmental components. Cigarette smoking, for example, doubles the risk of heart attack. The new research suggests that the roughly 25 percent of Caucasians who have inherited two copies of the “risk variant” have a 40 to 60 percent increased risk of heart disease, as compared with someone who doesn’t carry the variant at all. “It is a very big risk factor … almost up to the level of smoking and a little bit greater than elevated cholesterol,” says Stefansson.

The other team of researchers, led by Ruth McPherson, director of the lipid clinic and lipid research laboratory at the University of Ottawa Heart Institute, in Canada, and Jonathan Cohen, a geneticist at the University of Texas Southwestern Medical Center, in Dallas, focused its search on severe, premature cases of heart disease that struck before age 60. Both reports appear in the May 4 issue of the journal Science.

Although heart disease is highly inheritable, says McPherson, the genetic variations that increased disease risk were largely unknown. To this end, both teams cast a wide net by using whole genome association studies to identify genetic risk factors. The method involves screening the DNA of two groups of individuals–those with coronary-artery disease, and healthy controls with no signs of disease–against a collection of common genetic variations called single nucleotide polymorphisms (SNPs). The scientists then search for particular SNPs that are associated with the disease more often than not.

McPherson’s team used DNA samples from four different populations, comprising a total of 23,000 individuals, and screened them using approximately 100,000 SNPs. The researchers discovered a strong association between two of these genetic variants on chromosome 9 and risk of early heart disease. Scientists at DeCode conducted a higher-resolution scan using about 300,000 SNPs and five populations, totaling 17,000 individuals, and identified three SNPs with significant ties to heart disease.

Regardless of the differences between the studies, the fundamental findings are the same, both McPherson and Stefansson stress.

The researchers anticipate that the identification of the variant will lead to new DNA-based diagnostic tests that could identify young people at high risk for heart disease. With a new test, physicians could potentially select the high-risk patients who would benefit most from lifestyle changes and drugs like aspirin, statins, and the like. This is a disease for which there are “good preventive therapies,” says McPherson.

The newly identified genetic risk variant is not actually a gene; rather, it’s a segment of DNA that falls in the vicinity of two genes previously implicated in cancer. “Our experience is that almost all these variants that predispose to the common diseases are not in the coding sequence of genes,” says Stefansson. “They are outside the coding sequence and influence expression. I’m not surprised to find them some distance away from genes.”

In just the past week, the location of the risk variant has become a hot spot in the genome. Four independent teams, including DeCode, published reports linking the same region on chromosome 9 to diabetes.

“I think this is a stunner,” says Francis Collins, director of the National Human Genome Research Institute, in Bethesda, MD, and leader of one of the four teams, during a seminar on genome-wide association studies. “This is like the seat of the soul of the genome. It seems like this one place carries all of that weight for two very common and very dangerous diseases.”