The ENPP1 Q121 Variant Predicts Major Cardiovascular Events in High-Risk Individuals: Evidence for Interaction With Obesity in Diabetic Patients

Insulin resistance (IR) and cardiovascular disease may share a common genetic background. We investigated the role of IR-associated ENPP1 K121Q polymorphism (rs1044498) on cardiovascular disease in high-risk individuals

Genetic variability at the leptin receptor ( LEPR) locus is a determinant of plasma fibrinogen and C-reactive protein levels

Cellular and animal studies suggest that leptin has proinflammatory and prothrombotic effects that could link increased adipose mass directly to atherogenesis. To investigate this hypothesis, we examined the effect of genetic variability at the leptin receptor ( LEPR) locus on the plasma levels of fibrinogen and CRP—two markers of inflammation and susceptibility to atherosclerosis. Linkage disequilibrium analysis of 71 single-nucleotide polymorphisms (SNPs) spanning the LEPR locus revealed four haplotype blocks that could be tagged by 11 SNPs. In 630 healthy Caucasian individuals, variability in block #4 was significantly associated with plasma fibrinogen ( p = 0.005), accounting for 3% of its variance ( r 2 = 0.030). The same block was also associated with CRP levels ( p = 0.049, r 2 = 0.022). The effect was strongest for two of the SNPs in this block. At rs3790432, fibrinogen was 10% higher in minor allele homozygotes than in major allele homozygotes and intermediate in heterozygotes ( p = 0.015). At rs1805096, it was 5% higher ( p = 0.007) and CRP 32% higher ( p = 0.011) in major allele homozygotes than in minor allele carriers. This pattern of association was also evident in the haplotype analysis. Association of leptin receptor variability with inflammatory traits supports the hypothesis that leptin may play a role in atherogenesis

The type 2 diabetes and insulin-resistance locus near IRS1 is a determinant of HDL cholesterol and triglycerides levels among diabetic subjects

Objective: SNP rs2943641 near the insulin receptor substrate 1 (IRS1) gene has been found to be associated with type 2 diabetes (T2D) and insulin-resistance in genome-wide association studies. We investigated whether this SNP is associated with cardiovascular risk factors and coronary artery disease (CAD) among diabetic individuals. Methods: SNP rs2943641 was typed in 2133 White T2D subjects and tested for association with BMI, serum HDL cholesterol and triglycerides, hypertension history, and CAD risk. Results: HDL cholesterol decreased by 1 mg/dl (p = 0.004) and serum triglycerides increased by 6 mg/dl (p = 0.016) for each copy of the insulin-resistance allele. Despite these effects, no association was found with increased CAD risk (OR = 1.00, 95% CI 0.88-1.13). Conclusions: The insulin-resistance and T2D locus near the IRS1 gene is a determinant of lower HDL cholesterol among T2D subjects. However, this effect is small and does not translate into a detectable increase in CAD risk in this population. (C) 2011 Elsevier Ireland Ltd. All rights reserved

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

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. (C) 2011 Elsevier Ireland Ltd. All rights reserved

Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes.

IMPORTANCE: Diabetes is associated with an elevated risk of coronary heart disease (CHD). Previous studies have suggested that the genetic factors predisposing to excess cardiovascular risk may be different in diabetic and nondiabetic individuals. OBJECTIVE To identify genetic determinants of CHD that are specific to patients with diabetes. DESIGN, SETTING, AND PARTICIPANTS: We studied 5 independent sets of CHD cases and CHD-negative controls from the Nurses' Health Study (enrolled in 1976 and followed up through 2008), Health Professionals Follow-up Study (enrolled in 1986 and followed up through 2008), Joslin Heart Study (enrolled in 2001-2008), Gargano Heart Study (enrolled in 2001-2008), and Catanzaro Study (enrolled in 2004-2010). Included were a total of 1517 CHD cases and 2671 CHD-negative controls, all with type 2 diabetes. Results in diabetic patients were compared with those in 737 nondiabetic CHD cases and 1637 nondiabetic CHD-negative controls from the Nurses' Health Study and Health Professionals Follow-up Study cohorts. Exposures included 2 543 016 common genetic variants occurring throughout the genome. MAIN OUTCOMES AND MEASURES: Coronary heart disease - defined as fatal or nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or angiographic evidence of significant stenosis of the coronary arteries. RESULTS: A variant on chromosome 1q25 (rs10911021) was consistently associated with CHD risk among diabetic participants, with risk allele frequencies of 0.733 in cases vs 0.679 in controls (odds ratio, 1.36 [95%CI, 1.22-1.51]; P = 2 × 10-8). No association between this variant and CHD was detected among nondiabetic participants, with risk allele frequencies of 0.697 in cases vs 0.696 in controls (odds ratio, 0.99 [95%CI, 0.87-1.13]; P = .89), consistent with a significant gene x diabetes interaction on CHD risk (P = 2 × 10-4). Compared with protective allele homozygotes, rs10911021 risk allele homozygotes were characterized by a 32%decrease in the expression of the neighboring glutamate-ammonia ligase (GLUL) gene in human endothelial cells (P = .0048). A decreased ratio between plasma levels of γ-glutamyl cycle intermediates pyroglutamic and glutamic acid was also shown in risk allele homozygotes (P = .029). CONCLUSION AND RELEVANCE: A single-nucleotide polymorphism (rs10911021) was identified that was significantly associated with CHD among persons with diabetes but not in those without diabetes and was functionally related to glutamic acid metabolism, suggesting a mechanistic link