Are You Genetically Vulnerable to Heart Disease (NOS3)?

The NOS3 gene codes for a protein also called NOS3, short for nitric oxide synthase 3. NOS3 is most abundant in the inner lining of the blood vessels, where it produces nitric oxide (NO) from the amino acid arginine [R, R].

NO is a messenger molecule with multiple functions in the immune and nervous systems. Additionally, NOS3-derived NO increases blood flow and lowers the risk of heart disease [R, R].

Vessel Relaxation

In the blood vessels, NO activates a pathway that decreases the amount of free calcium. The low free calcium levels cause vessel relaxation [R, R].

Alternatively, NO breaks down the free radical superoxide, both directly and by activating an antioxidant enzyme. By protecting the lining tissue from this molecule, it preserves its function and prevents vessel stiffness [R, R].

However, NO production must be tightly fine-tuned. Very high amounts may react with the superoxide anion and form the even more harmful peroxynitrite [R].

Prevention of Clogged Arteries

NO diffuses across platelet membranes and increases cGMP levels in these cells. By doing so, it prevents platelets from being activated and clumping together inside the arteries [R, R].

Immune cells may bind to platelets and further increase the risk of artery-clogging. NO blocks the major inflammatory hub NF-kB, thus preventing white blood cells from attaching to the vessels and ending up bound to platelets [R, R].

Some conditions are characterized by the overgrowth of smooth muscle cells in the vessels, which may contribute to artery-clogging. NO increases cGMP production, which blocks cell growth [R].

Alternatively, the antioxidant effect of NO reduces LDL damage by free radicals and prevents cholesterol buildup in the vessels [R].

The NOS3 gene is responsible for producing NO. This messenger molecule relaxes the blood vessels and prevents their clogging, thus increasing blood flow and protecting the heart.

Primary SNP: NOS3 rs1799983

• ‘G’ = Normal risk of heart disease
• ‘T’ = Increased blood pressure and risk of heart disease (especially coronary heart disease)

Population Frequency:

• Almost 70% of the world population has ‘GG’
• In people with European ancestry, the frequency of the ‘T’ allele is increased to 34%

Other Important SNPs:

NOS3 rs2070744

• ‘T’ = Normal risk of heart disease
• ‘C’ = Increased risk of heart attack and coronary heart disease

Population Frequency:

• Approximately 60% of the world population have ‘TT’
• The frequency of the ‘TT’ genotype is reduced to 30% in European descendants

NOS3 rs3918226

• ‘C’ = Normal risk of heart disease
• ‘T’ = Increased risk and severity of heart and coronary disease

Population Frequency:

• 94% of the world population have ‘CC’
• 17% of people with European ancestry have ‘CT’ and only 1% have ‘TT’

Among the different NOS3 polymorphisms, rs179983 has been most widely studied. In terms of heart function, it’s preferable to have the ‘GG’ genotype (as around 70% of the population does). The ‘T’ variant produces a protein that can’t reach its activation sites in cell membranes, ultimately decreasing NO production [R].

The ‘T’ allele was associated with an increased risk of coronary heart disease and heart attack in several studies. It’s also more frequent in children with congenital heart disease and predicts a faster progression of heart damage in people with diabetes [R, R, R, R].

However, NO is a double-edged sword and the overproducing ‘GG’ genotype may also have negative effects on the heart. It’s associated with reduced heart function in people with kidney disease, increased risk of death in those with high blood pressure, and heart failure in African-Brazilians [R, R, R].

Another SNP, rs2070744, is also linked to heart attack and coronary heart disease. Almost 40% of people carry at least one copy of the ‘C’ allele, which can be bound by a protein that blocks NOS3 production [R, R, R].

Finally, the ‘T’ allele of rs3918226 also results in lower NOS3 levels and is associated with a higher risk and severity of heart and coronary events. Fortunately, this allele is extremely rare and most people (81-99%) have the ‘CC’ genotype [R, R, R].

Two NOS3 polymorphisms, rs179983 and rs2070744, are the main ones associated with heart and coronary disease. The minor allele of rs3918226 also increases the risk, but this mutation is very rare.

By Increasing Risk Factors

The ‘T’ allele of rs179983 is a good predictor of high blood pressure, especially in Chinese populations. Nevertheless, some studies failed to find this association and suggested that factors such as the geographic origin or fat intake were much more influential [R, R, R, R, R, R].

This allele is also linked to a higher risk of artery-clogging, probably because it increases vessel stiffness and blood cholesterol (both free and bound to LDL) [R, R, R].

The minor ‘C’ allele of rs2070744 was also associated with high blood pressure, possibly by reducing the levels of adiponectin, a protein that lowers blood pressure. Intriguingly, this allele increased vessel stiffness in Japanese women but not in men [R, R, R].

Although rs179983 and rs2070744 are generally considered to predict an increased risk of high blood pressure during pregnancy (pre-eclampsia), not all studies found this association [R, R, R].

Three studies on over 5,000 people associated the minor ‘T’ allele at rs3918226 with increased blood pressure and artery stiffness [R, R, R].

By Interfering with Medical Therapies

Your NOS3 variant may determine your risk of complications from medical procedures. Concretely, the minor allele of rs179983 increased the risk of coronary artery narrowing (restenosis), blood clot formation in the veins, and irregular heart rate after surgery [R, R, R].

Variations in this gene may also reduce the effectiveness of conventional and alternative therapies. The minor ‘T’ allele of rs3918226 predicted a worse response to the diuretic chlorthalidone in people with high blood pressure. Similarly, a treatment made from red sage roots (salvianolate injection) was less effective in people with the ‘T’ allele of rs179983 [R, R].

The NOS3 polymorphisms mainly increase the risk of heart disease through their association with higher blood pressure, cholesterol levels, and artery stiffness. Some of them may also interfere with medical therapies.