Researchers have identified a previously unknown genetic locus (the place a gene occupies on a chromosome) significantly associated with increased coronary heart disease risk among patients with type 2 diabetes, but the association was not found in persons without diabetes. The study in the August 28 issue of JAMA shows that the variant is functionally related to glutamic acid metabolism, suggesting a mechanistic link.
"The prevalence of type 2 diabetes has been steadily increasing in the United States and other countries, with the total number of affected people reaching more than 370 million globally. Long-term cardiovascular complications, and especially coronary heart disease (CHD), are the principal causes of morbidity and mortality among diabetic patients," according to background information in the article. "Diabetes is associated with an elevated risk of CHD. Previous studies have suggested that the genetic factors predisposing to excess cardiovascular risk may be different in diabetic and nondiabetic individuals."
Lu Qi, M.D., Ph.D., of the Harvard School of Public Health, Boston, and colleagues conducted a study to identify genetic determinants of CHD that are specific to patients with diabetes. The researchers studied 5 independent sets of CHD cases and CHD-negative controls from the Nurses' Health Study (enrolled in 1976 and followed up through 2008), Health Professionals Follow-up Study (enrolled in 1986 and followed up through 2008), Joslin Heart Study (enrolled in 2001-2008), Gargano Heart Study (enrolled in 2001-2008), and Catanzaro Study (enrolled in 2004-2010). Included were a total of 1,517 CHD cases and 2,671 CHD-negative controls, all with type 2 diabetes. Results in patients with diabetes were compared with those in 737 nondiabetic CHD cases and 1,637 nondiabetic CHD-negative controls from the Nurses' Health Study and Health Professionals Follow-up Study cohorts.
Of the 2,543,016 genetic variants that were tested for association with CHD in stage 1 of the 3-stage genome-wide analysis, 26 met the criterion for promotion to stage 2, and 3 of these further met the criterion for promotion to stage 3. Of the 3 variants that were promoted to stage 3, a variant on chromosome 1q25 (rs10911021) was consistently associated with CHD risk among diabetic participants. No association between this variant and CHD was detected among nondiabetic participants.
"The locus is in the region of the GLUL gene on chromosome 1q25 and may affect CHD risk by reducing the expression of this gene and affecting glutamate and glutamine metabolism in endothelial cells. This genetic variant appeared to be specifically associated with CHD in the diabetic population and showed a significant gene-by-diabetes synergism on CHD risk," the authors write. "... further studies are needed to fully understand the biological mechanisms linking it to CHD in diabetes."