Interaction Between Poor Glycemic Control and 9p21 Locus on Risk of Coronary Artery Disease in Type 2 Diabetes

Context A common allele on chromosome 9p21 has been repeatedly associated with increased risk of coronary artery disease ( CAD) in the general population. However, the magnitude of this effect in the population with diabetes has not been well characterized. Objective To examine the association of the 9p21 variant with CAD in individuals with type 2 diabetes and evaluate its interaction with poor glycemic control. Design, Setting, and Participants ( 1) Case- control study of 734 type 2 diabetes patients ( 322 with angiographically diagnosed CAD and 412 with no evidence of CAD) who were recruited between 2001 and 2006 at the Joslin Clinic, Beth Israel Deaconess Medical Center; and ( 2) independent cohort study of 475 type 2 diabetes patients from the Joslin Clinic whose survival status was monitored from their recruitment between 1993 and 1996 until December 31, 2004. Participants for both studies were genotyped for a representative single- nucleotide polymorphism at 9p21 ( rs2383206) and characterized for their long- term glycemic control by averaging multiple hemoglobin A(1c) ( HbA(1c)) measurements taken in the years before study entry. Main Outcome Measures For the case- control study, association between single-nucleotide polymorphism rs2383206 and CAD defined as angiographically documented stenosis greater than 50% in a major coronary artery or a main branch thereof was assessed and for the cohort study, cumulative 10- year mortality was documented. Results Individuals who were homozygous for the risk allele were significantly more frequent among case than control participants ( 42.3% vs 28.9P=. 0002). This association was unaffected by adjustment for cardiovascular risk factors, but the effect of the risk genotype was significantly magnified ( adjusted P for interaction=. 048) in the presence of poor glycemic control ( worst tertile of the distribution of HbA(1c) at examination). Relative to the CAD risk for patients with neither a 9p21 risk allele nor poor glycemic control, the CAD odds for participants having 2 risk alleles but not poor glycemic control were increased 2- fold ( odds ratio [ OR], 1.99; 95% confidence interval [ CI], 1.17- 3.41), whereas the odds for study participants with the same genotype and with poor glycemic control were increased 4- fold ( OR, 4.27; 95% CI, 2.26- 8.01). The interaction was stronger ( adjusted P=. 005) when a measure of long- term glycemic control ( 7- year average rather than most recent HbA(1c)) was used with ORs of 7.83 ( 95% CI, 3.49- 17.6) for participants having 2 risk alleles and a history of poor glycemia and 1.54 ( 95% CI, 0.72- 3.30) for participants with the same genotype but without this exposure. A similar interaction between 9p21 variant and poor glycemic control was observed with respect to cumulative 10- year mortality in the cohort study ( 43.6% in patients with 2 risk alleles and poor glycemic control, 23.1% in individuals with only the 2 risk alleles, 30.0% in individuals with only poor glycemic control, and 31.6% in individuals with neither factor, P for interaction, =. 036). Conclusion In this study population, the CAD risk associated with the 9p21 variant was increased in the presence of poor glycemic control in type 2 diabetes.