rs3918226 — NOS3

NOS3 promoter variant that reduces eNOS expression and increases hypertension risk by disrupting an ETS transcription factor binding site

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The eNOS Promoter Switch — How rs3918226 Dials Down Nitric Oxide

Endothelial nitric oxide synthase (eNOS), encoded by NOS3, is the enzyme that keeps blood vessels relaxed and healthy. By producing nitric oxide (NO) in the inner lining of blood vessels, eNOS lowers blood pressure, prevents clot formation, and dampens inflammation. rs3918226 sits in the promoter region of NOS3 — the stretch of DNA that acts as a volume control for how much enzyme the cell makes.

The Mechanism

The rs3918226 T allele disrupts a binding site for ETS transcription factors11 ETS transcription factors
E-twenty six (ETS) proteins are a family of transcription factors that activate gene expression by binding specific DNA sequences in promoters in the NOS3 promoter. When the T allele is present, ETS factors bind less effectively, and the cell transcribes less NOS3 mRNA. Cell experiments confirm that the T allele reduces eNOS promoter activity by 20–40% compared to the reference C allele. Less eNOS means less nitric oxide, which means blood vessels are less able to relax on demand — a direct path to higher blood pressure and endothelial dysfunction.

This variant is distinct from two other well-studied NOS3 polymorphisms: rs2070744 (T-786C, a second promoter variant) and rs1799983 (Glu298Asp, a missense variant affecting enzyme stability). All three reduce NO bioavailability through different mechanisms and can interact when present together.

The Evidence

A genome-wide association study22 genome-wide association study
Salvi E et al. Genomewide association study identifies novel essential hypertension susceptibility locus. Hypertension, 2012 combining 21,714 subjects found rs3918226 to be among the strongest genetic predictors of essential hypertension identified to date: OR 1.34 (95% CI 1.25–1.44; P = 1.032 × 10⁻¹⁴), with each T allele adding approximately 1.9 mmHg systolic and 1.4 mmHg diastolic blood pressure on average.

A follow-up prospective study33 prospective study
Salvi E et al. Target sequencing, cell experiments, and a population study establish eNOS gene as hypertension susceptibility gene. Hypertension, 2013 in 2,722 European adults followed for 7.6 years showed that TT homozygotes experienced a blood pressure rise of 9.7/6.8 mmHg (systolic/diastolic) compared to 3.8/1.9 mmHg in C-allele carriers. Among the 2,013 who were normotensive at baseline, TT homozygosity conferred a hazard ratio of 2.04 (95% CI 1.24–3.37; P = 0.005) for developing hypertension — a doubling of risk. The T allele is rare globally (5–8% frequency) but enriched in European populations (~8%), where the hypertension burden is also high.

Practical Actions

Because this variant reduces eNOS transcription rather than enzyme function, approaches that supply nitric oxide through alternative pathways are particularly relevant. Dietary nitrates from beetroot, spinach, arugula, and celery are converted by oral bacteria to nitrite, and then to NO in the acidic environment of the stomach and blood — entirely bypassing eNOS. This pathway has been shown to lower blood pressure by 4–10 mmHg in clinical trials of high-nitrate diets.

Antioxidant support matters because reduced eNOS activity can shift the enzyme toward producing superoxide (oxidative stress) rather than NO — a state called eNOS uncoupling. Vitamin C helps recycle the eNOS cofactor BH4, keeping what enzyme is present in its NO-producing mode.

Blood pressure monitoring is actionable: a sustained reading above 130/80 mmHg warrants discussion with a clinician about pharmacological support. CT/TT carriers on antihypertensive medications may respond differently to drug classes that modulate NO signaling, as shown by pharmacogenomic studies of this locus.

Interactions

rs3918226 can interact with the nearby NOS3 promoter variant rs2070744 (T-786C) and the coding variant rs1799983 (Glu298Asp) to produce compounded reductions in NO bioavailability. Carriers of the T allele at rs3918226 who also carry the C allele at rs2070744 and/or the T allele at rs1799983 face additive risk from multiple independent impairments to eNOS expression and enzyme stability. These interactions are described in the Salvi 2013 study and in haplotype analyses of NOS3 variants in migraine and cardiovascular disease cohorts.

Nutrient Interactions

dietary nitrates increased_need
vitamin C increased_need

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal eNOS Expression Normal

Normal eNOS promoter activity and nitric oxide production

You carry two copies of the common C allele at rs3918226. Your NOS3 promoter binds ETS transcription factors normally, producing typical amounts of eNOS enzyme and nitric oxide. This is the most common genotype globally (~89% of people) and is not associated with increased hypertension risk from this locus.

CT Reduced eNOS Expression Intermediate

One copy of the promoter variant — moderately reduced eNOS output

Heterozygous CT carriers occupy an intermediate position between full eNOS expression (CC) and the substantially impaired TT state. The prospective Salvi 2013 cohort showed that the dominant effect of the T allele (CT and TT combined versus CC) was associated with meaningfully higher blood pressure trajectories over 7.6 years. The hypertension risk is further amplified when CT co-occurs with the T-786C variant (rs2070744) or the Glu298Asp missense variant (rs1799983), since these represent independent hits on eNOS expression and enzyme stability.

TT Impaired eNOS Expression Reduced

Two copies of the promoter variant — substantially reduced eNOS output and doubled hypertension risk

The TT genotype causes the most pronounced impairment of eNOS transcription from this locus. With 20–40% less eNOS protein, the endothelium produces substantially less nitric oxide, impairing vasodilation and elevating vascular tone. The attributable risk of TT for incident hypertension was estimated at 51% in the Salvi 2013 cohort, meaning half of the hypertension events in TT carriers were attributable to this genotype.

Because the TT genotype is so rare (~7 per 1,000 people), it has not been widely studied in isolation. Most of the HR 2.04 estimate comes from a small subgroup (n=28 TT individuals in the Salvi cohort) and should be interpreted with appropriate uncertainty. The directional evidence is consistent across multiple studies, however, and the functional mechanism (reduced promoter activity) is confirmed in cell experiments. If you also carry risk alleles at rs2070744 or rs1799983, your cumulative NOS3 impairment is substantially higher than any single variant predicts.