The K121Q Polymorphism of the ENPP1/PC-1 Gene Is Associated With Insulin Resistance/Atherogenic Phenotypes, Including Earlier Onset of Type 2 Diabetes and Myocardial Infarction

The K121Q Polymorphism of the ENPP1/PC-1 Gene Is Associated With Insulin Resistance/Atherogenic Phenotypes, Including Earlier Onset of Type 2 Diabetes and Myocardial Infarction Simonetta Bacci 1 , Ornella Ludovico 1 , Sabrina Prudente 2 , Yuan-Yuan Zhang 3 , Rosa Di Paola 1 , Davide Mangiacotti 1 , Anna Rauseo 1 , David Nolan 3 , Jill Duffy 3 , Grazia Fini 1 , Lucia Salvemini 1 , Cesare Amico 4 , Carlo Vigna 4 , Fabio Pellegrini 5 , Claudia Menzaghi 1 , Alessandro Doria 3 and Vincenzo Trischitta 1 6 1 Unit of Endocrinology, CSS Scientific Institute, San Giovanni Rotondo, Italy 2 CSS-Mendel Institute, Rome, Italy 3 Research Division, Joslin Diabetes Center and the Departments of Medicine, Harvard Medical School, Boston, Massachusetts 4 Unit of Cardiology, CSS Scientific Institute, San Giovanni Rotondo, Italy 5 Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, S. Maria Imbaro, Italy 6 Department of Clinical Sciences, University La Sapienza, Rome, Italy Address correspondence and reprint requests to Simonetta Bacci, MD, Unit of Endocrinology, CSS Scientific Institute, Viale Cappuccini 1, San Giovanni Rotondo (FG), Italy. E-mail: dnnwba{at}tin.it ; or Vincenzo Trischitta, MD, Mendel–CSS Institute, Viale Regina Margherita, 261, 00198, Rome, Italy. E-mail: vincenzo.trischitta{at}uniroma1.it Abstract 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 the 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 in