title: Joint effect of insulin signaling genes on cardiovascular events and on whole body and endothelial insulin resistance.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Clinical Unit of Endocrinology, IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Bacci
authors.forename: Sabrina
authors.initials: S
authors.lastname: Prudente
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Copetti
authors.forename: Belinda
authors.initials: B
authors.lastname: Spoto
authors.forename: Stefano
authors.initials: S
authors.lastname: Rizza
authors.forename: Roberto
authors.initials: R
authors.lastname: Baratta
authors.forename: Natalia
authors.initials: N
authors.lastname: Di Pietro
authors.forename: Eleonora
authors.initials: E
authors.lastname: Morini
authors.forename: Rosa
authors.initials: R
authors.lastname: Di Paola
authors.forename: Alessandra
authors.initials: A
authors.lastname: Testa
authors.forename: Francesca
authors.initials: F
authors.lastname: Mallamaci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tripepi
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zhang
authors.forename: Luana
authors.initials: L
authors.lastname: Mercuri
authors.forename: Sara
authors.initials: S
authors.lastname: Di Silvestre
authors.forename: Renato
authors.initials: R
authors.lastname: Lauro
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Malatino
authors.forename: Agostino
authors.initials: A
authors.lastname: Consoli
authors.forename: Fabio
authors.initials: F
authors.lastname: Pellegrini
authors.forename: Assunta
authors.initials: A
authors.lastname: Pandolfi
authors.forename: Lucia
authors.initials: L
authors.lastname: Frittitta
authors.forename: Carmine
authors.initials: C
authors.lastname: Zoccali
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Trischitta
mesh_terms: D002318:Cardiovascular Diseases / Q000235:genetics*; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D006801:Humans; D007328:Insulin / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D011446:Prospective Studies; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D007328:Insulin