title: The SH2B1 obesity locus is associated with myocardial infarction in diabetic patients and with NO synthase activity in endothelial cells.
abstract: OBJECTIVE
  Obesity and cardiovascular disease recognize a common metabolic soil and may therefore share part of their genetic background. Genome-wide association studies have identified variability at the SH2B1 locus as a predictor of obesity. We investigated whether SNP rs4788102, which captures the entire SH2B1 variability, is associated with coronary artery disease (CAD) and/or myocardial infarction (MI) in patients with type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  SNP rs4788102 was typed in 2015 White subjects with T2DM from three CAD case-control studies [n=740 from the Gargano Hearth Study (GHS, Italy); n=818 from the Joslin Hearth Study (JHS, Boston); n=457 from the University of Catanzaro (CZ, Italy)].
  
  
  RESULTS
  SNP rs4788102 (G/A) was not associated with CAD (overall allelic OR=1.06, 95% CI=0.93-1.21; p=0.37). On the contrary, it was associated with MI in GHS (1.42, 1.12-1.81; p=0.004) and in the three samples analyzed together (1.21, 1.04-1.41; p=0.016). Insulin stimulated nitric oxide synthase (NOS) activity in human vein endothelial cells from G/G (n=4, p=0.03) but not the G/A (n=5, p=0.83) genotype. Of the SNPs in perfect LD with rs4788102, one (rs7498665) affects amino acid polarity (Ala484Thr) and falls into a highly conserved protein segment of SH2B1 containing a class II SH3 domain binding site.
  
  
  CONCLUSIONS
  Variability at the SH2B1 obesity locus is associated with MI in diabetic patients and with reduced insulin-stimulated NOS activity in human endothelial cells. Further studies are needed to replicate this association and dissect the biology underlying this finding.
authors: IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy. s.prudente@css-mendel.it
authors: Sabrina
authors: S
authors: Prudente
authors: Eleonora
authors: E
authors: Morini
authors: Jay
authors: J
authors: Larmon
authors: Francesco
authors: F
authors: Andreozzi
authors: Natalia
authors: N
authors: Di Pietro
authors: Angela
authors: A
authors: Nigro
authors: Ernest V
authors: EV
authors: Gervino
authors: Gaia Chiara
authors: GC
authors: Mannino
authors: Simonetta
authors: S
authors: Bacci
authors: Thomas H
authors: TH
authors: Hauser
authors: Emanuele
authors: E
authors: Bellacchio
authors: Gloria
authors: G
authors: Formoso
authors: Fabio
authors: F
authors: Pellegrini
authors: Vittoria
authors: V
authors: Proto
authors: Claudia
authors: C
authors: Menzaghi
authors: Lucia
authors: L
authors: Frittitta
authors: Assunta
authors: A
authors: Pandolfi
authors: Giorgio
authors: G
authors: Sesti
authors: Alessandro
authors: A
authors: Doria
authors: Vincenzo
authors: V
authors: Trischitta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D001900:Boston; D016022:Case-Control Studies; D019295:Computational Biology; D003324:Coronary Artery Disease / Q000201:enzymology / Q000235:genetics; D048909:Diabetes Complications / Q000201:enzymology / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007558:Italy; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009765:Obesity / Q000235:genetics*; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007328:Insulin; C518910:SH2B1 protein, human; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III