Obesity is one of the world’s greatest public health challenges affecting not only developed, but also developing countries. The presence of obesity has now been conclusively linked to heightened morbidity and mortality through increased risk for many chronic diseases, including type-2 diabetes, hypertension, dyslipidemia, and coronary artery disease [1
]. The pathogenesis of obesity is multifactorial incorporating both genetics and lifestyle. In children, obesity is associated with increased risk for multifaceted derangements in metabolic and cardiovascular function, including endothelial dysfunction (ED) [5
]. In general terms, overweight children are more likely to prematurely develop ED, hypertension and type 2 diabetes, an array of conditions that would normally be only found in older obese adults [4
]. Recently, we have shown that obesity in children is associated with an increased risk for the development of ED prior to the onset of hypertension [7
]. However, not every obese child will develop ED, suggesting that both genetic and environmental factors may play a role. Conversely, a small subset of otherwise healthy children who are not obese may manifest abnormal endothelial function, and such functional phenotype may be determined by genetic variance in endothelial function-related genes.
ED, an early risk marker of cardiovascular disease, refers to a loss of normal homeostatic function in the blood vessels and is characterized by altered vasodilatory and vasoconstrictive functions and inflammatory activity [9
]. ED is involved in the development of vascular complications related to dyslipidemia, and cardiovascular disease such as hypertension, coronary artery disease and chronic heart failure [10
]. A major contributor of ED involves reductions in the amount of bioavailable nitric oxide (NO) in the vasculature [12
]. Indeed, NO is an important factor in endothelial functional homeostasis, and also inhibits platelet aggregation, leukocyte adhesion, smooth muscle cell migration and proliferation [13
], as well as oxidation of atherogenic low-density lipoprotein [14
]. NO is synthesized from the amino acid L-arginine in endothelial cells, as well as many other cell types by three nitric oxide synthase (NOS) isoforms; neuronal (nNOS, NOS1), inducible (iNOS, NOS2), and endothelial (eNOS, NOS3) [15
]. NOS1 and NOS3 genes are constitutively expressed resulting in a low basal synthesis of NO [19
], whereas induction of NOS2 expression is regulated by transcription factors such as nuclear factor κB (NF-K
]. Several studies have examined the possibility that genetic variants in the genes encoding these enzymes could influence their expression and functional activity, potentially altering the predisposition to cardiovascular disease [22
]. Accordingly, single nucleotide polymorphisms (SNPs) have been identified in NOS genes, and their association with coronary artery disease, hypertension, and diabetes has been explored [24
]. To the best of our knowledge, the potential associations between NOS polymorphisms and ED are currently unexplored in children.
The endothelin (EDN) system consists of three endothelin isoforms (EDN1, EDN2 and EDN3), and two receptors (endothelin type A and type B) linked to multiple signaling pathways [27
]. Endothelins (EDN1, EDN2 and EDN3) are 21-amino acid peptides that exert their effects through their cognate receptors EDNRA and EDNRB with different degrees of binding affinity. Various SNPs have been identified on EDN genes and EDNRA and EDNRB receptors genes, and have been associated with susceptibility and prognosis of diseases such as heart failure, dilated cardiomyopathy, diabetic retinopathy, and atherosclerosis [28
]. Again, we are unaware of any published studies on the potential associations between ED and endothelin-related gene variants in children.
Based on aforementioned considerations, we aimed to identify single nucleotide polymorphisms (SNPs) in NOS family (3 isoforms), and EDN family (3 isoforms and their 2 cognate receptors) in order to identify potential associations of these SNPs with ED in children.