Link observed between genetic variation, CAD in type 2 diabetes

Genetic variant combined with history of poor glycemic control may predict those at high risk for CAD.

Poor glycemic control and the 9p21 variant increased the risk for coronary artery disease in patients with type 2 diabetes, according to findings recently published in JAMA.

“By combining the 9p21 genetic variant with a history of poor glycemic control, it may be possible to identify a subgroup of individuals with type 2 diabetes who are at especially high risk for CAD and who should be targeted with aggressive interventions,” Alessandro Doria, MD, PhD, MPH, associate professor of medicine, at Joslin Diabetes Center and Harvard Medical School, told Endocrine Today.

“This might be especially important if an intervention is difficult to implement, is expensive or has important side effects,” he said.

Doria and colleagues conducted two studies to examine the association between the genetic variant and CAD and to determine whether the association is affected by poor glycemic control.

One study included patients with type 2 diabetes with angiographically diagnosed CAD (n=322) or no evidence of CAD (n=412) recruited between 2001 and 2006. Another study included patients with type 2 diabetes (n=475) whose survival status was monitored from recruitment during 1993 to 1996 until Dec. 31, 2004.

Gene variation increased risk

Compared with the CAD risk for patients who did not have a 9p21 risk gene variant or poor glycemic control, the risk for CAD among patients with two risk gene variants but without poor glycemic control increased twofold, according to the researchers; the odds for CAD among patients with the same genotype but poor glycemic control increased fourfold.

The researchers found a stronger interaction when a measure of long-term glycemic control was used for patients with two risk gene variants and a history of poor glycemia and for patients with the same genotype but without long-term poor glycemia.

“We were surprised to see that the effect of the 9p21 variant on CAD was actually greater, rather than smaller, among individuals with diabetes,” Doria said. “Individuals with diabetes who had both factors had a risk for CAD up to eight times higher than that of individuals with diabetes who had neither factors.”

“This finding may have implications for our understanding of atherogenesis 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 researchers wrote.

“We are entering the age of personalized medicine, in which the genetic profile will help doctors decide the best therapy for each patient and this is an example of what may lie ahead,” Doria said. – by Christen Haigh

JAMA. 2008;300:2389-2397.

Although the clinical value in predicting an increased risk for cardiovascular disease based on genotype remains unclear, especially when other strong clinical risk factors exist, it is very interesting to consider the implications of this study in overall cardiovascular risk in type 2 diabetes. The absence of a clear correlation between cardiovascular mortality and glycemic control in type 2 diabetes has been a troubling finding in the recent literature. This study suggests that a subset of diabetic patients homozygous for this risk allele do in fact have a twofold increased risk for cardiovascular mortality with worsening glycemic control. This implies that dilution of these large studies with multiple genotypes masks the effect of a smaller susceptible population.

– Dawn Belt Davis, MD, PhD

Endocrine Today Editorial Board member