It is the first genome-wide association study (GWAS) to identify a novel genetic variant associated with coronary heart disease (CHD) in people with type 2 diabetes, who have a two- to four-fold higher risk of heart disease compared with those without diabetes. The finding could lead to new interventions aimed at preventing or treating CHD among patients with type 2 diabetes.
“This is a very intriguing finding because this variant was not found in previous genome-wide association studies in the general population,” said lead author Lu Qi, assistant professor in the HSPH Department of Nutrition and assistant professor at the Channing Division of Network Medicine, Brigham and Women’s Hospital. “This means that the genetic risk factors for cardiovascular disease may be different among those with and without diabetes.”
“The identification of this genetic variant opens up the possibility of developing treatments that are specifically aimed at breaking the links between diabetes and CHD,” said co-lead author Alessandro Doria, associate professor in the Department of Epidemiology at HSPH and a researcher at Joslin Diabetes Center.
The study appears online August 27 and will appear in the August 28, 2013 issue of JAMA (Journal of the American Medical Association).
More than 370 million people worldwide have type 2 diabetes and CHD is the leading cause of death among diabetic patients. Overall CHD-related mortality has been declining in the United States and other industrialized countries over the past few decades. But CHD deaths that are diabetes-related are on the rise because of the increasing prevalence of the latter ailment. Although prior genome-wide studies have found many genetic variants for CHD in people in the general population, no such study had examined genetic determinants for CHD specifically in those with type 2 diabetes.
For their analysis, the researchers used data from several long-term studies: the Nurses’ Health Study, the Health Professionals Follow-up Study, the Joslin Heart Study, and two Italian studies—the Gargano Heart Study and the Catanzaro Study. They looked at 4,188 diabetic patients, including 1,517 with CHD and 2,671 without CHD as a control group.
Testing more than 2.5 million genetic variants, the researchers found that a variant near the GLUL gene, a gene that encodes a key enzyme regulating the conversion of glutamic acid to glutamine, was consistently associated with a 36% increased risk of CHD in people with diabetes. There was no association between this variant and CHD risk in study participants without diabetes.
They also found that the variant may interfere with the expression of a gene that regulates blood levels of amino acids involved in insulin secretion and glucose metabolism—key functions that go awry in those with type 2 diabetes.
Since these amino acids are nutrients affected by food intake, it’s possible that changes in diet may help reduce increased CHD risk among people with diabetes. The finding may also provide scientists with other targets for therapies to help prevent or treat CHD in diabetic patients.
Other HSPH and Channing researchers 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.
“Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in type 2 diabetes,” Lu Qi, Qibin Qi, Sabrina Prudente, Christine Mendonca, Francesco Andreozzi, Natalia di Pietro, Mariella Sturma, Valeria Novelli, Gaia Chiara Mannino, Gloria Formoso, Ernest V. Gervino, Thomas H. Hauser, Jochen D. Muehlschlegel, Monika A. Niewczas, Andrzej S. Krolewski, Gianni Biolo, Assunta Pandolfi, Eric Rimm, Giorgio Sesti, Vincenzo Trischitta, Frank Hu, and Alessandro Doria, JAMA, online August 27, 2013
For more information:
About 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 and the classroom 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. For more information, visit www.hsph.harvard.edu.
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 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 30‐plus faculty‐level 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 www.joslinresearch.org.