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). DESIGN AND SETTING: 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.
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). DESIGN AND SETTING: 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 SH2B1obesity locus is associated with MI in diabeticpatients 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: Stephen S Rich; Donald W Bowden; Steven M Haffner; Jill M Norris; Mohammed F Saad; Braxton D Mitchell; Jerome I Rotter; Carl D Langefeld; Lynne E Wagenknecht; Richard N Bergman Journal: Diabetes Date: 2004-07 Impact factor: 9.461
Authors: Meian He; Marilyn C Cornelis; Paul W Franks; Cuilin Zhang; Frank B Hu; Lu Qi Journal: Arterioscler Thromb Vasc Biol Date: 2009-11-12 Impact factor: 8.311
Authors: Muredach P Reilly; Mingyao Li; Jing He; Jane F Ferguson; Ioannis M Stylianou; Nehal N Mehta; Mary Susan Burnett; Joseph M Devaney; Christopher W Knouff; John R Thompson; Benjamin D Horne; Alexandre F R Stewart; Themistocles L Assimes; Philipp S Wild; Hooman Allayee; Patrick Linsel Nitschke; Riyaz S Patel; Nicola Martinelli; Domenico Girelli; Arshed A Quyyumi; Jeffrey L Anderson; Jeanette Erdmann; Alistair S Hall; Heribert Schunkert; Thomas Quertermous; Stefan Blankenberg; Stanley L Hazen; Robert Roberts; Sekar Kathiresan; Nilesh J Samani; Stephen E Epstein; Daniel J Rader Journal: Lancet Date: 2011-01-14 Impact factor: 79.321
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