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

Abstract

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 diabetic patients (322 with angiographically-diagnosed CAD and 412 with no evidence of CAD) who were recruited in 2001–2006 at the Joslin Clinic/Beth Israel Deaconess Medical Center, 2. Independent cohort study of 475 type 2 diabetic patients from the Joslin Clinic whose survival status was monitored from their recruitment in 1993–1996 until December 31, 2004. Study subjects were genotyped for a representative SNP at 9p21 (rs2383206) and characterized for their long-term glycemic control by averaging multiple hemoglobin A1c (HbA1c) measurements taken in the years before study entry. Main Outcome Measures Case-control study: association between SNP rs2383206 and CAD defined as angiographically documented stenosis greater than 50% in a major coronary artery or a main branch thereof. Cohort study: cumulative 10-year mortality. Results Individuals homozygous for the risk allele were significantly more frequent in case than control subjects (42.3 vs. 28.9%, p=0.0002). This association was unaffected by adjustment for cardiovascular risk factors, but the effect of the risk genotype was significantly magnified (adjusted p for interaction = 0.048) in the presence of poor glycemic control (worst tertile of the distribution of HbA1c at examination). Relative to the CAD risk for patients with neither a 9p21 risk allele nor poor glycemic control, the CAD risk for subjects having two risk alleles but not poor glycemic control was increased two-fold (OR=1.99, 1.17–3.41), whereas the risk for study subjects with the same genotype and with poor glycemic control was increased four-fold (OR=4.27, 2.26–8.01). The interaction was stronger (adjusted p=0.005) when a measure of long-term glycemic control (7-year average rather than most recent HbA1c) was used, with ORs of 7.83 (3.49–17.6) for subjects having two risk alleles and a history of poor glycemia and 1.54 (0.72–3.30) for subjects 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 two risk alleles and poor glycemic control, 23.1% in those with only the two risk alleles, 30.0% in those with only poor glycemic control, and 31.6% in those with neither factor, p for interaction=0.036). Conclusions 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.

Interaction of ADIPOQ Genetic Polymorphism With Blood Pressure and Plasma Cholesterol Level on the Risk of Coronary Artery Disease

“…Recently, a similar interaction has been observed between the 9p21 locus and poor glycemic control on the risk of CAD. 38 These findings demonstrate the complex interactions between genetic factors and traditional CAD risk factors in the development of atherosclerosis.…”

Impact of Electronic Health Record Clinical Decision Support on Diabetes Care: A Randomized Trial

“…As personalization of chronic disease care increases in the coming era of genomic medicine, EHR-embedded clinical decision support may become an essential tool needed to systematically process complex risk prediction data and then accurately identify appropriate clinical goals and high-priority treatment options for each patient at each clinical encounter. 36,37 In this study, the use of EHR-based clinical decision support technology was reinforced by changes in clinic rooming procedures, changes in nurse roles, and provision of incentives to physicians and clinic staffelements that were lacking in previous failed attempts to implement EHR-based clinical decision support. Physicians were provided clinical decision support information immediately before the start of the visit to facilitate visit planning.…”

Chromosome 9p21 polymorphism is associated with myocardial infarction but not with clinical outcome in Han Chinese

“…Several prospective studies have shown that chromosome 9p21 variation was associated with development of atherosclerosis and incident cardiovascular disease (14)(15)(16). However, Chen et al revealed that 9p21 conferred null effects on the severity or progression of coronary atherosclerosis in Caucasians (17).…”