NOS3 Genetic variants and Inflammation in Type 2 Diabetes: A Nutrigenetic Pilot Study

Abstract

Nutrigenomics is a newly developed science domain which studies the relation between the different nutrients and the genes. The term refers to both the study of how the foods we consume affect our genes and how our genes can influence our body‘s response to what we eat. It has been proposed and then scientifically proved that the genes are flexible and that the genes products behave differently in the presence of certain nutrients. Recent scientific discoveries relating specific gene variants to dietary response can enable physicians to use nutrition to its fullest potential to address various health issues. These personalized diets can optimize an individual‘s nutritional status and specifically focus on preventing diet-related diseases (Fenech et al., 2011). One of these genes that showed genetic variations is Nitric Oxide Synthase 3 (NOS3) gene encoded on chromosome 7q35-36. It is responsible for the production of Nitric Oxide Synthase (NOS) enzyme that mediates the production of Nitric Oxide (NO) from L-arginine in the endothelial cells (Liu et al., 2005). NO is an important endothelium-derived vascular relaxing factor (Hibi et al., 1998). The replacement of guanine by thymine at NOS3 nucleotide 894 results in a change of amino acid from glutamate to aspartate at codon 298 of the mature NOS3 protein. Two groups of investigators have shown that NOS3 with aspartate at position 298 is subject to selective proteolytic cleavage which is predicted to result in absence or reduction of NOS activity in  Introduction 2 homozygous carriers of the 894T allele (Persu et al., 2002). This results in defects in endothelial cell function and NO production being described for subjects with atherosclerosis, hypertension, diabetes, as well as obesity. Obesity has previously been associated with diabetes risk in several studies, and obese individuals have been reported to have reduced NO bioavailability compared to controls whose weight is in the normal range (Bressler et al., 2013). In addition, adipose tissue is one of the main sources of inflammatory mediators, with Interleukin-6 (IL6) among them (Eder et al., 2009). It has also been demonstrated that IL6 inhibits NOS activation (Hung et al., 2010). The relation of NOS3 genetic variants and metabolic diseases has been studied. For example, in one study, the relationship between the G894T polymorphism and diabetes risk was modified by BMI with evidence for interaction between obesity and the minor genotype. In subsequent analyses stratified by levels of BMI, homozygosity for the NOS3 894T allele in obese individuals was shown to be significantly associated with an increased risk for diabetes when compared to the most common genotype, while no variation in susceptibility with genotype was found for individuals whose BMI was less than 30 kg/m2 (Bressler et al., 2013). In another study, both