Gene variations explain why people with type 2 diabetes are at much greater risk for coronary artery disease

New studies by an international team of scientists led by Joslin Diabetes Center have found variations in a gene that help explain why people with type 2 diabetes are at much greater risk for coronary artery disease, the leading cause of death for this group.

"We now have potential gene markers to help identify diabetes patients at increased risk for heart disease," said Alessandro Doria, M.D., Ph.D., Investigator in Joslin's Genetics and Epidemiology research section, Director of Joslin's Genetics Core and Assistant Professor of Medicine at Harvard Medical School. "This knowledge could potentially lead to drugs or other methods that affect this pathway, reducing risk of heart attack and stroke in these patients."

An estimated 18 million people in the United States have type 2 diabetes. People with diabetes are two to four times more likely to have cardiovascular disease, and are at increased risk for stroke, blindness, kidney disease and nerve damage.

In a two-part study published in the Oct. 1 edition of the British journal Human Molecular Genetics, Dr. Doria and his colleagues at Joslin and other research centers in the Northeast and researchers in Italy focused on a gene governing a protein called CD36. This protein is found in the membrane of several types of cells, including the walls of blood vessels.

Previous studies had shown that, among other functions, CD36 is involved in transporting free fatty acids into cells. It also is a scavenger of oxidized "bad" cholesterol LDL at the arterial wall. All are major players in contributing to atherosclerosis -- the dangerous buildup of plaque that can lead to partial or complete blockage of the artery, leading to heart attack or stroke.

In the first part of this study, the researchers mapped the structure of the CD36 gene, which consists of hundreds of nucleic acids strung together like beads on a spiral necklace. They were looking for variants in this sequence that are associated with increased risk of heart disease.

Studying 585 people who did not have diabetes, the researchers found five different CD36 variations that were associated with increased levels of free fatty acids and triglycerides. When all five variants were factored together, a strong link emerged -- the highest levels of fatty acids and triglycerides occurred in people with a specific variant combination.

Using this new knowledge as a basis for a second study, they studied 518 people in both the United States and Italy. All had type 2 diabetes. In addition, nearly half of these subjects also had heart disease, as shown by heart catheterization indicating more than 50 percent blockage of at least one coronary artery. The others did not have any visible heart disease.

The researchers mapped out each person's CD36 gene variations, then compared those results with the presence of known heart disease. Again, there was a strong link: People with that specific variant combination in the CD36 gene were 60 percent more likely to have heart disease.

"While this research is a significant starting point for assessing risk of heart disease, a constellation of factors are involved," said Dr. Doria. "But it is clear that in addition to high blood pressure, high cholesterol and environmental factors such as smoking, genes are important determinants of heart disease in people with type 2 diabetes."