Gene Variation For Diabetics Associated With Increased Risk of Coronary Artery Disease

Among the known risk factors for cardiovascular disease, diabetes mellitus ranks as one of the most potent. It increases the lifetime risk of a major cardiac event by 2 to 4 times, relative to individuals without diabetes, according to background information in the article. A substantial proportion of cardiovascular risk is under the control of genetic factors.

Genetic variation on chromosome 9p21 has been associated with increased risk of coronary artery disease (CAD) in the general population. Alessandro Doria, M.D., Ph.D., M.P.H., of the Joslin Diabetes Center, Harvard Medical School, Boston, and colleagues examined the association of this genetic variant with coronary artery disease in individuals with type 2 diabetes and whether the association is affected by poor glycemic control. The researchers conducted two studies, with one including 734 type 2 diabetes patients (322 with angiographically diagnosed CAD and 412 with no evidence of CAD), who were recruited between 2001 and 2006; the other study included 475 type 2 diabetes patients whose survival status was monitored from their recruitment between 1993 and 1996 until December 31, 2004.

Participants for both studies were tested for a representative single-nucleotide polymorphism (gene variation) of chromosome 9p21 (rs2383206) and characterized for their long-term glycemic control by averaging measurements of hemoglobin A1c (HbA1c) taken in the years before study entry.

The researchers found that relative to the CAD risk for patients with neither a 9p21 risk gene variant nor poor glycemic control, the odds for CAD among participants having two risk gene variants but not poor glycemic control was increased 2-fold, whereas the odds for CAD among study participants with the same genotype but poor glycemic control was increased 4-fold. The interaction was stronger when a measure of long-term glycemic control (7-year average rather than most recent HbA1c) was used for participants having two risk gene variants and a history of poor glycemia and for participants with the same genotype but not long-term poor glycemia.

A similar interaction between the 9p21 variant and poor glycemic control was observed with respect to the rate of death after 10 years.

“In conclusion, 9p21 [variant] and poor glycemic control interact in determining the odds of CAD in type 2 diabetes. This finding may have implications for our understanding of atherogenesis [the process of plaque forming in arteries] in diabetes and for the design of more effective prevention strategies. More broadly, it illustrates the complex etiology of multifactorial disorders and highlights the importance of accounting for gene-environment and gene-gene interactions in the quest for genetic factors contributing to these conditions,” the authors write.

JAMA. 2008;300[20]:2389-2397.