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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

Gene Dosage of the Common Variant 9p21 Predicts Severity of Coronary Artery Disease

John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada

Manuscript received August 11, 2009; revised manuscript received September 23, 2009, accepted October 29, 2009.

^_* Reprint requests and correspondence: Dr. Alexandre F. R. Stewart, University of Ottawa Heart Institute, 40 Ruskin Street, H3100, Ottawa, Ontario K1Y 4W7, Canada (Email: astewart{at}ottawaheart.ca).

Objectives: The purpose of this study was to test the hypothesis that 9p21 gene dosage determines the severity of coronary artery disease (CAD).

Background: The 9p21 locus is the first common genetic variant to associate with risk of CAD and/or myocardial infarction in multiple studies.

Methods: A cross-sectional study examined nondiabetic patients with CAD defined by coronary angiography to have at least 1 epicardial stenosis >50%. In all, 950 patients with early onset CAD (age 56.1 ± 9.6 years) and an independent sample of 764 patients with late onset CAD (age 70.0 ± 8.0 years) were enrolled from the cardiac catheterization laboratories at the University of Ottawa Heart Institute from April 15, 2006, to August 15, 2008, and genotyped for the single nucleotide polymorphism rs1333049 9p21 risk variant. Angiographers were blinded to genotype. The association between 9p21 risk genotype and the proportion of patients with 3-vessel disease, 1-vessel disease, left main trunk disease, and coronary artery bypass graft surgery was tested, as was its association with the modified Gensini and Duke coronary scoring indexes.

Results: Among younger CAD cases, 3-vessel disease demonstrated a strong, direct association with 9p21 gene dosage (p = 4.26 x 10^–4). Conversely, 1-vessel disease demonstrated a strong inverse association with increasing gene dosage (p = 2.41 x 10^–5). In the replication sample, gene dosage also predicted 3-vessel disease (p = 6.51 x 10^–6). Left main trunk disease and coronary artery bypass graft surgery demonstrated a direct strong association with gene dosage (p = 3.66 x 10^–4) and (p = 2.42 x 10^–2), respectively. Gene dosage demonstrated a strong, direct association with both the modified Gensini (p < 0.0001) and modified Duke (p = 3 x 10^–4) coronary scores. Risk variant 9p21 did not associate with myocardial infarction once stratified for disease severity.

Conclusions: Gene dosage of the common risk variant 9p21 predicts the severity of coronary atheromatous burden.

Key Words: coronary artery disease • genetics • risk assessment

Abbreviations and Acronyms   BMI = body mass index   CABG = coronary artery bypass graft surgery   CAD = coronary artery disease   CI = confidence interval   LAD = left anterior descending artery   MI = myocardial infarction   OR = odds ratio

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