BOSTON -- August 27, 2013 -- Joslin scientists, in collaboration with researchers from the Harvard School of Public Health and Italian research institutes, have identified a previously unknown genetic variant associated with an increased risk of coronary heart disease (CHD) in type 2 diabetic patients. This discovery has the potential to lead to the development of new treatments for CHD in diabetic patients. The findings appear in the [month] issue of 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.
About Joslin Diabetes Center
Joslin Diabetes Center, located in Boston, Massachusetts, is the world's largest diabetes research and clinical care organization. Joslin is dedicated to ensuring that people with diabetes live long, healthy lives and offers real hope and progress toward diabetes prevention and a cure. Joslin is an independent, nonprofit institution affiliated with Harvard Medical School.
Our mission is to prevent, treat and cure diabetes. Our vision is a world free of diabetes and its complications. For more information, visit http://www.joslin.org.
About Joslin Research
Joslin Research comprises the most comprehensive and productive effort in diabetes research under one roof anywhere in the world. With 30plus facultylevel investigators, Joslin researchers focus on unraveling the biological, biochemical and genetic processes that underlie the development of type 1 and type 2 diabetes and related complications.
Joslin research is highly innovative and imaginative, employing the newest tools in genetics, genomics and proteomics to identify abnormalities that may play a role in the development of diabetes and its complications. Joslin Clinic patients, and others with diabetes, have the option of participating in clinical trials at Joslin to help translate basic research into treatment innovations.
Joslin has one of the largest diabetes training programs in the world, educating 150 M.D. and Ph.D. researchers each year, many of whom go on to head diabetes initiatives at leading institutions all over the globe. For more information, visit http://www.joslinresearch.org.
About the Harvard School of Public Health
Harvard School of Public Health brings together dedicated experts from many disciplines to educate new generations of global health leaders and produce powerful ideas that improve the lives and health of people everywhere. As a community of leading scientists, educators, and students, we work together to take innovative ideas from the laboratory to people's lives—not only making scientific breakthroughs, but also working to change individual behaviors, public policies, and health care practices. Each year, more than 400 faculty members at HSPH teach 1,000-plus full-time students from around the world and train thousands more through online and executive education courses. Founded in 1913 as the Harvard-MIT School of Health Officers, the School is recognized as America's first professional training program in public health.