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 cap...

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Published in:Atherosclerosis 2011-12, Vol.219 (2), p.667-672
Main Authors: Prudente, Sabrina, Morini, Eleonora, Larmon, Jay, Andreozzi, Francesco, Di Pietro, Natalia, Nigro, Angela, Gervino, Ernest V, Mannino, Gaia Chiara, Bacci, Simonetta, Hauser, Thomas H, Bellacchio, Emanuele, Formoso, Gloria, Pellegrini, Fabio, Proto, Vittoria, Menzaghi, Claudia, Frittitta, Lucia, Pandolfi, Assunta, Sesti, Giorgio, Doria, Alessandro, Trischitta, Vincenzo
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Aged
amino acids
atherosclerosis
Atherosclerosis (general aspects, experimental research)
binding sites
Biological and medical sciences
Blood and lymphatic vessels
Blood vessels and receptors
Boston
Cardiology. Vascular system
Cardiovascular
Case-Control Studies
Computational Biology
Coronary artery disease
Coronary Artery Disease - enzymology
Coronary Artery Disease - genetics
Diabetes Complications - enzymology
Diabetes Complications - genetics
Diabetes Mellitus, Type 2 - complications
Diabetes Mellitus, Type 2 - enzymology
Diabetes Mellitus, Type 2 - genetics
endothelial cells
Female
Fundamental and applied biological sciences. Psychology
Gene Frequency
Genetic Association Studies
genetic background
Genetic Predisposition to Disease
Genetic risk factors
Human Umbilical Vein Endothelial Cells - enzymology
Humans
insulin
Insulin - metabolism
Insulin resistance
Italy
Linkage Disequilibrium
loci
Logistic Models
Male
Medical sciences
Middle Aged
Myocardial infarction
Myocardial Infarction - enzymology
Myocardial Infarction - genetics
nitric oxide synthase
Nitric Oxide Synthase Type III - metabolism
noninsulin-dependent diabetes mellitus
obesity
Obesity - genetics
Odds Ratio
patients
Phenotype
Polymorphism, Single Nucleotide
Polymorphisms
Risk Assessment
Risk Factors
single nucleotide polymorphism
soil
Type 2 diabetes mellitus
Vertebrates: cardiovascular system
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Summary: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). 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.
ISSN:0021-9150
1879-1484
DOI:10.1016/j.atherosclerosis.2011.08.019