Objective:To conduct a stage I study to identify genetic predictors of coronary artery disease severity and develop genomic profiles for accurate classification of high- risk patients in a clinical cohort. Methods:719 patients who underwent coronary angiography for myocardial infarction or suspected coronary artery disease were divided into cases with severe disease and controls with non-severe and no disease. Coronary artery disease severity was scored on based on; i) severity of coronary artery luminal stenosis and ii) number of diseased main coronary vessels. A case-control design was employed. We directly assessed for SNP association with coronary artery disease severity as determined by invasive coronary angiography Results:A systematic statistical analysis strategy was used to assess the association of all genetic factors with CAD severity. Results of this analysis revealed two SNPs associated with severity of coronary artery stenosis and 3 SNPs associated with number of diseased proximal vessels. Logistic regression models were generated for each SNP factoring in related covariates – age, sex, dyslipidemia and hypertension status. (rs12526453) in the PHACTR1 gene on chromosome 6, and (rs6725887) in the WDR12 gene on chromosome 2 were predictive of the severity of coronary artery disease luminal stenosis after adjustment for cofactors (OR=1.38 p=0.02 and OR=1.46 p= 0.048 respectively). (rs6725887) was again associated with CAD severity as determined by the number of diseased proximal vessels (OR=2.01, p=0.004). Two further SNPs were also associated with CAD severity as defined by the number of diseased proximal vessels: (rs4977574) in proximity to CDK2A & CDK2B genes on chromosome 9p21.3 (OR=1.64 p=.005); and (rs10953541) in the (BCAP29 gene on chromosome 7 (OR=1.814, p=.004). Conclusion:We have identified four SNPs to be predictive of CAD severity as assessed by coronary angiography. Two SNPs are predictive of the severity of proximal coronary artery disease based on the extent of luminal stenosis: (rs12526453) in the PHACTR1 gene on chromosome 6 and (rs6725887) in the WDR12 gene on chromosome 2. (rs6725887) and a further two SNPs are predictive of triple vessel disease: (rs4977574) in the ANRIL gene in proximity to CDK2A &CCK2B on chromosome 9p21.3 and (rs10953541) in the BCAP29 gene on chromosome 7. This discovery may pave the way for the development of a genetic diagnostic and screening tool for coronary atherosclerosis. It may also help identify targets for future gene therapeutics against atherosclerotic coronary disease.