Insulin resistance (IR) is pathogenic for type 2 diabetes and coronary artery disease (CAD). The K121Q polymorphism of the ENPP1/PC-1 gene is associated with IR. Our aim was to investigate the role of the 121Q variant on the risk of type 2 diabetes and CAD. Nondiabetic control subjects (n ‫؍‬ 638), type 2 diabetic patients without CAD (n ‫؍‬ 535), and type 2 diabetic patients with CAD (n ‫؍‬ 434) from Italy and the U.S. were studied. The proportion of 121Q carriers progressively increased in

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... three groups (27.4, 28.8, and 33.2%, respectively; adjusted P value ‫؍‬ 0.027). Among diabetic patients (n ‫؍‬ 969), 121Q carriers had an increased risk of developing type 2 diabetes before the age of 65 years (adjusted odds ratio [OR] 2.26, 95% CI 1.26 -4.03; P ‫؍‬ 0.006) and having a myocardial infarction (MI) (n ‫؍‬ 156) by 50 years of age (3.17, 1.46 -6.88, P ‫؍‬ 0.007). The 121Q variant was also associated with an increased risk for CAD (1.47, 1.01-2.18; P ‫؍‬ 0.049) in diabetic patients who did not smoke (n ‫؍‬ 546). In conclusion, the ENPP1/PC-1 121Q variant is associated with a progressive deterioration of the IR-atherogenic phenotype; among diabetic individuals, it is also associated with earlier onset of type 2 diabetes and MI.