rs1799983 — NOS3 Glu298Asp

NOS3 Glu298Asp - Nitric Oxide and Cardiovascular Health

Endothelial nitric oxide synthase (eNOS), encoded by the NOS3 gene, produces nitric oxide (NO) in the lining of blood vessels. Nitric oxide is one of the most important molecules in cardiovascular biology - it relaxes blood vessel walls, prevents blood clots from forming, and reduces inflammation in the arterial lining.

The Mechanism

The Glu298Asp ¹¹ Glutamic acid to aspartic acid at position 298 variant (rs1799983) replaces glutamic acid with aspartic acid at position 298 of the eNOS protein. The T allele (Asp) makes the enzyme more susceptible to cleavage and degradation, reducing the steady-state amount of functional eNOS in endothelial cells. Less enzyme means less nitric oxide production, which can lead to stiffer blood vessels, higher blood pressure, and increased oxidative stress.

The Uncoupling Problem

When eNOS is impaired, it can become "uncoupled" ²² Uncoupled eNOS produces harmful superoxide instead of beneficial nitric oxide - instead of producing beneficial nitric oxide, it generates superoxide, a harmful reactive oxygen species. This switches the enzyme from being protective to actively damaging. Adequate levels of BH4 ³³ BH4 is an essential cofactor that keeps eNOS in its coupled, NO-producing state (tetrahydrobiopterin), a critical cofactor, help prevent uncoupling.

The Evidence

A large meta-analysis⁴⁴ large meta-analysis
Casas JP et al. Endothelial Nitric Oxide Synthase Genotype and Ischemic Heart Disease. Circulation, 2004 of 26 studies involving 23,028 individuals confirmed that the TT genotype is associated with increased risk of ischemic heart disease (OR 1.31, 95% CI 1.13-1.51). A subsequent meta-analysis of 60 studies⁵⁵ meta-analysis of 60 studies
Association between eNOS rs1799983 polymorphism and hypertension. BMC Cardiovasc Disord, 2021 involving 14,185 hypertension cases and 13,407 controls found significant associations under all genetic models (TT vs GG: OR 1.80, 95% CI 1.41-2.31). The effect is more pronounced when combined with the NOS3 promoter variant (rs2070744) and lifestyle factors like smoking, sedentary behavior, and poor diet.

Practical Implications

Dietary nitrates from beets, spinach, and arugula can boost NO production through an alternative pathway ⁶⁶ Oral bacteria convert dietary nitrate to nitrite, which is then reduced to NO in the acidic stomach environment that bypasses eNOS entirely. Regular aerobic exercise is one of the most potent stimulators of eNOS activity and NO production. Vitamin C and other antioxidants help prevent eNOS uncoupling by supporting BH4 recycling.