Genetic variant associated with coronary heart disease in type 2 diabetes

The findings appear in the Journal of the American Medical Association (JAMA).

CHD is the leading cause of morbidity and mortality among diabetic patients. Diabetic individuals have a two- to threefold increased risk for CHD and two- to fourfold higher CHD morbidity and mortality rates. In people with diabetes, CHD occurs at a younger age. While overall mortality rates of CHD have been declining in the U.S., the number of CHD deaths in the diabetic population has escalated as the prevalence of the disease has increased.

It has been known for years that genetic factors influence susceptibility to CHD in the general population. However, studies have suggested that the genetic factors related to CHD risk may be different in the diabetic population. Investigating genetic variants related to cardiovascular disease in diabetes is an active area of research in the Section on Genetics and Epidemiology at Joslin.

The scientists were interested in finding out whether there were genetic determinants of CHD specific to diabetic patients. In collaboration with colleagues from the Harvard School of Public Health and research institutes in Italy, they conducted genome-wide association analyses of 1,517 type 2 diabetic patients with CHD and 2,671 type 2 diabetic subjects without CHD. They compared the results to analyses of 737 non-diabetic participants with CHD and 1,637 non-diabetic participants without CHD. The participants were selected from the Nurses Heath Study, Health Professionals Follow-up Study, Joslin Heart Study, Gargano Heart Study and Catanzaro Study.

A genetic variant in the region of the GLUL gene was identified that is associated with an increased risk of CHD in type 2 diabetics. "It is a common genetic variant that becomes important in the presence of diabetes. You need the presence of both diabetes and the variant to increase the risk of CHD," says Alessandro Doria, M.D., Ph.D., M.P.H., co-senior author and an Investigator in the Section on Genetics and Epidemiology, Associate Professor of Medicine at Harvard Medical School, and Associate Professor in the Department of Epidemiology at the Harvard School of Public Health. The other senior author for the study is Lu Qi, M.D., Ph.D., of the Harvard School of Public Health.

"This finding may have particularly important implications regarding prevention and reduction of cardiovascular morbidity and mortality through dietary and lifestyle intervention in diabetic patients," said Dr. Qi.

The genetic variant may affect CHD risk by reducing the expression of the GLUL gene which is involved in glutamine/glutamic acid metabolism. Research evidence indicates that glutamine/glutamic acid metabolism contributes to the regulation of insulin secretion and glucose metabolism. Several clinical trials suggest that glutamine may protect against cardiovascular disease. In addition, epidemiological studies have shown that abnormal metabolism of these amino acids is related to insulin resistance, type 2 diabetes and cardiovascular disorders. Further research is needed to better understand the relationship of glutamine/glutamic acid metabolism to the development of CHD. "It may give us new insights into the mechanisms underlying the increased risk of CHD in diabetic individuals and enable us to identify targets for new cardioprotective drugs that are specific for the diabetic population," says Dr. Doria.

Joslin scientists are currently investigating whether there are other genetic variants that specifically predispose type 2 diabetic subjects to cardiovascular disease and are planning to expand this research to investigate genetic variants associated with CHD in the type 1 diabetes population. "If we find additional variants, we may be able to develop a tool that identifies diabetic patients who are at increased risk of developing CHD and focus on preventing the disease in these people," says Dr. Doria.

Other researchers from the Harvard School of Public Health involved in the study included Eric Rimm, associate professor of epidemiology and nutrition; Frank Hu, professor of nutrition and epidemiology; and Qibin Qi, research fellow in the Department of Nutrition.

Funding for the study came from grants HL071981, DK091718, HL073168, DK046200 (Boston Obesity Nutrition Research Center), and DK36836 (Genetics Core of the Diabetes Research Center at Joslin Diabetes Center) from the National Institutes of Health, an American Heart Association Scientist Development Award (0730094N), a grant from the Italian Ministry of Health ('Ricerca Corrente 2011 e 2012'), and a grant from Fondazione Roma ('Sostegno alla ricerca scientifica biomedica 2008'). A portion of this work was conducted in a facility constructed with support from the National Institutes of Health Research Facilities Improvement Program (RR10600-01, CA62528-01, RR14514-01) from the National Center for Research Resources.