AbstractOBJECTIVE: Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity.DESIGN AND SETTING: 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose <126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs).RESULTS: 1. Risk variants jointly predicted cardiovascular events (HR = 1.181; p = 0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI (p = 0.006). 3. A significant association was also observed with ISI (p = 0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs (p = 0.009).CONCLUSIONS: Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies.
|Titolo:||Joint effect of insulin signaling genes on cardiovascular events and on whole body and endothelial insulin resistance|
|Data di pubblicazione:||2013|
|Citazione:||Joint effect of insulin signaling genes on cardiovascular events and on whole body and endothelial insulin resistance / Bacci, S; Prudente, S; Copetti, M; Spoto, B; Rizza, S; Baratta, R; Di Pietro, N; Morini, E; Di Paola, R; Testa, A; Mallamaci, F; Tripepi, G; Zhang, Yy; Mercuri, L; Di Silvestre, S; Lauro, R; Malatino, Lorenzo; Consoli, A; Pellegrini, F; Pandolfi, A; Frittitta, Lucia; Zoccali, C; Federici, M; Doria, A; Trischitta, V.. - In: ATHEROSCLEROSIS. - ISSN 0021-9150. - 226:1(2013), pp. 140-145.|
|Appare nelle tipologie:||1.1 Articolo in rivista|