The SH2B1 obesity locus is associated with myocardial infarction in diabetic patients and with NO synthase activity in endothelial cells

ObjectiveObesity 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 settingSNP 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)].ResultsSNP 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.ConclusionsVariability 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.