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Gene, Diet, Disease

NOS3 and Cardiovascular Health

About 50% of African and Caucasian and 20% of Asians carry at least one of the three diet-regulated hypertension-prone NOS3 minor alleles. These people are also more vulnerable to smoking hazards.

NOS3 gene encodes the enzyme endothelial nitric oxide synthase (eNOS), which catalyzes the formation of endogenous nitric oxide (NO) from the amino acid L-arginine (Fig. 1).

Figure 1. The production of endogenous NO from L-arginine catalyzed by eNOS. L-arginine is first converted to a stable intermediate N-hydroxyarginine (NHA), which is subsequently converted to L-citrulline and NO. In both conversions, oxygen and the reducing power molecule NADPH are the co-substrates.

Uncharged and ubiquitously present, the NO gas is a bioactive signaling molecule in human body. It is best known as a vasodilator thanks to the mechanistic studies of many blood pressure control medicines that function through the NO signaling pathways. Examples of these medicines include the widely used nitroglycerin against heart attack and the well known Viagra against erectile dysfunction. In addition, NO is also involved in the inhibition of platelets aggregation and adhesion, neuronal signal transmission, cytotoxicity against pathogens and tumors, coordination of heart rhythm and the regulation of cellular respiration activity.

Imbalance of the NO level leads to endothelial dysfunctions and many other diseases.  On one hand, reduction in basal NO release may predispose to hypertension, pre-eclampsia, thrombosis, vasospasm, atherosclerosis, and metabolic syndrome. On the other hand, high NO levels in circulating blood are associated with endotoxic shock, inflammation, acute hepatic dysfunction, glomerulonephritis, asthma, cardiomyopathy and a number of other disorders.

NOS3 encoded eNOS enzyme is critical for the NO level regulation in the cardiovascular system. Knockout mice deficient in eNOS developed hypertension as adults while transgenic mice over-expressing eNOS reduced blood pressure. Meanwhile, the eNOS+/- mice that have only one copy of the NOS3 gene are healthy under normal conditions but develop hypertension and insulin resistance under dietary stress such as high fat diet.

There are three common polymorphisms in the NOS3 gene that are associated with hypertension and other cardiovascular diseases: T-786C; VNTR 4b/a; and Glu298Asp.  The -786C and the Asp298 minor alleles are more common in Caucasians while the 4a minor allele is more common in African-Americans (Table 1). In African-Americans and Caucasians, 54% of the population carries at least one of the three minor alleles. In Asians, about 23% of the population carries at least one of the minor alleles. 

Table 1. Allele and genotype distribution among the major ethic groups. All the numbers represent percentage.

NOS3 Polymorphism African Americans Asian Caucasians Hispanics
T-786C Allele T 83.5 - 86.2 82.5 58.9 - 62.9 72.5 - 77.1
C 13.8 - 16.5 17.5 37.1 - 41.1 22.9 - 27.5
Genotype C/C 1.2 - 2.0 0 13.5 - 17.3 6.0 - 8.8
C/T 24.6 - 29.9 7 45.4 - 49.9 32.3 - 39.2
T/T 68.6 - 73.8 93 34.5 - 39.8 53.2 - 60.8
VNTR 4b/a Allele b 68 87-90 84  
a 26.5* 10 - 13 16
Genotype b/b 45 80-81 67-75
b/a 38 19-23 24-32
a/a 6 1-1.7 1
G894T (Glu298Asp) Allele G 85.3 - 88.3 90.3-92.6 65.6 - 69.3 78.4 - 82.3
T 11.7 - 14.7 8.6 30.7 - 34.4 17.7 - 21.6
Genotype G/G 71.8 - 77.7 81-91 42.4 - 48.6 61.6 - 68.2
G/T 21.2 - 27.1 9.0 - 19.0 40.8 - 47.1 27.9 - 33.9
T/T 0.7 - 1.6 0.2 - 0.7 9.2 - 12.1 3.2 - 5.4

Note: In the African American population, there is also 4% of 4c and 1.5% 4y minor alleles. See later sections for details.

The eNOS catalyzed NO biosynthesis is one of the most complicated reactions, requiring three co-substrates (L-arginine, NADPH, and O2) and five cofactors (flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), calmodulin (CaM), heme and tetrahydrobiopterin(BH4)). Many dietary factors regulate eNOS promoted NO production by modulating the bioavailability of these co-substrates and cofactors.  For example, the bioavailability of BH4, NADPH, FAD and FMN is regulated by redox balance, which is modulated by antioxidants found in fruits and vegetables. The biosynthesis of FAD and FMN is also depending on their precursor vitamin B2.  Three dietary minerals are directly involved in eNOS function: Fe2+ regulates the function of heme; Ca2+ regulates the function of CaM; and Zn2+ is directly involved in the interaction of eNOS and BH4.

Among the known dietary factors that regulate eNOS activity and NO production, significant interactions between sodium intake, antioxidants and fatty acids with the three common NOS3 polymorphisms have been reported. Dietary sodium regulates blood pressure and kidney function through the renin–angiotensin system that is described in the ACE and Blood Pressure review. A down-stream target of the renin–angiotensin system, bradykinin, regulates blood vessel dilatation through the NO signaling pathway.  High sodium level normally induced high blood pressure.  But for the -786C and the 4a minor allele carriers,  the degree of blood pressure increase in responding to high sodium is much greater.  Antioxidants compensate the lower eNOS level in the -786C minor allele and the Asp298 minor allele carriers. It has been proposed that ω-3 polyunsaturated fatty acids improves the membrane localization of the defective Asp298 enzyme, supported by the observation that blood triglycerides reduction by ω-3 polyunsaturated fatty acids supplementation was dramatic in the Asp298 minor allele carriers was not significant in the homozygous Glu/Glue genotype individuals.  Therefore, low sodium, high antioxidants (from fruits and vegetables) and increased ω-3 fatty acids are especially important for the minor allele carriers of these three polymorphisms to maintain an optimal eNOS function. L-arginine, the nitrogen donor in the NO production reaction, is generally abundant in protein rich diet and can be readily converted from other amino acids in human body. It is normally sufficient for the eNOS function. L-arginine supplement is NOT necessary unless recommended by medical doctors for clinically diagnosed symptoms.

Cigarette smoking induced stresses reduce the bioavailability of NO and impair the vascular dilatation function of eNOS.  It also interact with NOS3 polymorphisms by exacerbating the harmful effects in the minor allele carriers.  A range of 2- to 4-fold increased risks for smoking induced coronary heart disease have been reported for all of the three minor allele carriers, for whom it is strongly recommended to stay away from smoking.

In responding to physical exercise, minor allele carriers generally do not get as much health benefits as major allele genotypes carriers do. One exception is the male -786C allele carriers who response more favorably to aerobic exercise than the homozygous major allele 786TT genotype. Therefore, for most of the minor allele carriers (except -786C male), keep physical exercise at moderate level is recommended.

Taking all the information together, a guideline for NOS3 polymorphism specific diet regimen recommends (Table 2):

  • Avoid high sodium food for the -786C and VNTR 4a minor allele carriers
  • Increased fruits and vegetable proportion in the diet for the benefit of antioxidants for the -786C and Asp298 minor allele carriers.
  • Increase ω-3 fatty acids intake for the Asp298 minor allele carriers.
  • Avoid smoking for all minor allele carriers.
  • Keep physical exercise at moderate level for most of the minor allele carriers (except -786C male).

Table 2. The NOS3 gene minor allele specific dietary and exercise recommendation guidelines.

Factors -786C VNTR 4a Asp298
Sodium Decrease Decrease  
Antioxidant Increase   Increase
ω-3 fatty acids     Increase
Smoking Avoid Avoid Avoid
Exercise Moderate Moderate Moderate (women)

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