The purpose of this study was to test the hypothesis that 9p21 gene dosage determines the severity of coronary artery disease (CAD).The 9p21 locus is the first common genetic variant to associate with risk of CAD and/or myocardial infarction in multiple studies.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.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.Gene dosage of the common risk variant 9p21 predicts the severity of coronary atheromatous burden.

Background : Coronary artery disease (CAD) is the leading cause of death in the western world. The only common genetic risk locus identified to date by us and others in genome wide association studies (GWAS) resides at 9p21.3. Methods: The Ottawa Heart Genomic Study compared genotypes of 1,542 early onset CAD patients (average 49y) and 1,455 elderly control Caucasians (average 75y). Results: Here, we report two protective haplotypes in the 3′ region of the lipoprotein lipase (LPL) gene at 8p21.3. LPL promotes lipolysis of circulating triglycerides (TG) and increases levels of atheroprotective high density lipoprotein (HDL) cholesterol. Since the 8p21.3 haplotypes are protective, we tested their interaction with the 9p21.3 risk allele. The rs10503669 haplotype associated with elevated TG and HDL levels but did not affect risk from 9p21.3. In contrast, the rs17411031 haplotype was not associated with TG or HDL levels and showed a significant interaction that abolished 9p21.3 risk independent of known risk factors. The interaction was confirmed using data of the Wellcome Trust Case Control Consortium. Excluding carriers of the interacting allele, accuracy of 9p21.3 to predict CAD risk is dramatically improved. Conclusion: Identification of the first modifier gene of the 9p21.3 risk locus for CAD improves CAD risk assessment and provides novel insight into coronary atherosclerosis. This protective 8p21.3 locus may provide a target for novel therapy.

Background: The first common genetic risk variant for coronary artery disease (CAD), 9p21, was recently identified and shown to occur in 75% of Caucasian and Asian populations. However, 9p21 does not contain a protein coding gene and its function is unknown. Given the phenotypes of atherosclerosis and thrombosis, pursuit of the molecular mechanisms mediating 9p21 risk requires elucidation of the 9p21 phenotype. Accordingly, we tested the hypothesis that 9p21 is directly related to coronary atherosclerosis. Methods: We studied 709 patients who were prospectively enrolled from the coronary catheterization laboratory at the University of Ottawa Heart institute from April 15 th 2006 to 4 th January 2008. Each subject was genotyped for the single nucleotide polymorphism rs1333049 (risk allele located at 9p21). Patients were designated AA (risk/risk), AB (risk/non-risk) and BB (non-risk/non-risk). Angiograms were reviewed by two independent parties blinded to genotype. Lesions with 50% or more stenosis were considered significant for the purposes of this study. Odds ratios were generated for proportion of patients with 3VD, significant left main disease and CABG relative to the non-risk genotype, BB. Results: We demonstrated a strong direct association between 9p21 gene dosage and 3VD (Fig. 1A ). Conversely, a strong inverse association between 9p21 gene dosage and 1VD was observed (Fig. 1B ). A strong direct association between gene dosage and LM disease (Fig. 1C ) and CABG (Fig. 1D ) was seen. Conclusions: The 9p21 variant risk is mediated through deposition of coronary atheroma. Therefore, elucidating 9p21 function should target atherogenesis.

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.