EDN1 G2288T — The Endothelin Dial and Vascular Risk
Endothelin-1 (ET-1), encoded by the EDN1 gene on chromosome 6, is the most potent
endogenous vasoconstrictor known. It is produced primarily by vascular endothelial
cells and acts on smooth muscle to contract blood vessels, regulate blood pressure,
and modulate vascular tone across virtually every major vascular bed — pulmonary,
coronary, cerebral, and renal. ET-1 exerts its effects through two G-protein-coupled
receptor subtypes: ETA | endothelin receptor type A, expressed on smooth muscle,
mediating sustained vasoconstriction and
ETB, expressed on endothelial cells, mediating vasodilation and ET-1 clearance.
The balance between ET-1 production and receptor activation is a major determinant
of vascular resistance, and genetic variants that shift ET-1 output upward carry
measurable cardiovascular consequences.
The Mechanism
The rs2070699 variant sits 30 nucleotides into an intron of EDN1 at
chr6:12292539 (GRCh38), positioned downstream of exon 2. The functional consequence
is regulatory rather than protein-altering: the G-to-T substitution falls within a
conserved intronic region that influences pre-mRNA processing and EDN1 transcript
abundance. The PPHN study | Mei et al. EDN1 Gene Variant is Associated with
Neonatal Persistent Pulmonary Hypertension. Sci Rep. 2016
directly measured the downstream protein consequence: neonates carrying the T allele
at rs2070699 had significantly higher circulating ET-1 levels (3.33 ± 2.52 pg/mL
versus 1.22 ± 0.86 pg/mL; P=0.002), establishing that this intronic variant produces
a measurable upregulation of ET-1 expression.
Higher ET-1 impairs vasodilation on multiple levels. It directly promotes smooth muscle
contraction through ETA receptors, stimulates aldosterone secretion, activates platelet
aggregation, and — critically — reduces bioavailable nitric oxide (NO) by competing
with endothelium-derived vasodilatory signals. The NOx association documented by
Gumanova et al. 2019 | Gumanova et al. Levels of nitric oxide metabolites, adiponectin
and endothelin are associated with SNPs of the adiponectin and endothelin genes.
Biomed Rep. 2019 — rs2070699 associated
with reduced nitric oxide metabolite levels in women, which in turn predicted
cardiovascular mortality — captures this NO-ET-1 antagonism at the population level.
The Evidence
Neonatal pulmonary hypertension:
The clearest mechanistic link comes from
Mei et al. 2016 | Mei M et al. EDN1 Gene Variant is Associated with Neonatal
Persistent Pulmonary Hypertension. Sci Rep. 2016;6:29877,
a study of 112 neonates (55 PPHN cases, 57 controls) with respiratory distress.
The T allele appeared in 54.5% of PPHN cases versus 27.2% of controls
(OR 3.89, 95% CI 1.96–7.72), with TT homozygotes showing the highest ET-1 levels
and the longest mechanical ventilation requirements. This is the most direct evidence
linking rs2070699 to elevated ET-1 production, as PPHN results specifically from
failure of the pulmonary vasculature to dilate at birth — a process that requires
ET-1 levels to fall.
Cerebrovascular hemorrhage:
Foreman et al. 2017 | Foreman PM et al. Endothelin polymorphisms as a risk factor
for cerebral aneurysm rebleeding following aneurysmal subarachnoid hemorrhage.
Clin Neurol Neurosurg. 2017;157:65-69
prospectively followed 149 aSAH patients. The TT genotype emerged as an independent
predictor of aneurysm rebleeding (OR 97.4, 95% CI 3.83–2480, P=0.006), with all
five rebleed events occurring exclusively in TT carriers. While the sample is small
(n=149) and the CI wide, this result survived multivariable adjustment and aligns
biologically: elevated ET-1 promotes cerebral vasospasm and disrupts the vascular
wall biology that normally prevents rebleeding.
Ischemic stroke (sex-specific):
Zhang and Sui 2014 | Zhang L, Sui R. Effect of SNP polymorphisms of EDN1, EDNRA,
and EDNRB gene on ischemic stroke. Cell Biochem Biophys. 2014;70(3):1895-901
found that the G allele (not T) increased ischemic stroke risk in Northern Han Chinese
males (OR 1.78, 95% CI 1.15–2.75, P=0.009) — a finding that was sex-specific
(no association in females) and population-specific. This contradicts the direction
seen in the PPHN and rebleeding studies and likely reflects a different downstream
pathway or haplotype context in this population.
High-altitude physiology:
Yu et al. 2020 | Yu J et al. EDN1 gene potentially involved in the development of
acute mountain sickness. Sci Rep. 2020;10:5397
followed 356 male soldiers ascended to 3,700m, of whom 67% developed acute mountain
sickness. The T allele positively correlated with AMS occurrence, with rs2070699
surviving as an independent predictor in multivariate analysis alongside mean arterial
pressure, oxygen saturation, and lung function. ET-1 is upregulated in hypoxia,
and genetically elevated ET-1 may impair the hypoxic vasodilatory response in
pulmonary and cerebral vasculature.
Practical Actions
For TT homozygotes, the most actionable implication is monitoring of ET-1-dependent
vascular phenotypes. In clinical settings — particularly pulmonary hypertension,
cerebrovascular disease, or high-altitude exposure — the TT genotype provides context
for elevated cardiovascular reactivity. Endothelin receptor antagonists (bosentan,
ambrisentan, macitentan) are now standard therapy for pulmonary arterial hypertension,
and knowledge of rs2070699 genotype may inform clinical index of suspicion.
Nitric oxide precursors (L-arginine, L-citrulline) and dietary nitrates (beetroot,
leafy greens) support endogenous NO production, directly counteracting ET-1-mediated
vasoconstriction at the vascular endothelium. This is mechanistically targeted for
T allele carriers whose vascular tone is biased toward the ET-1 (vasoconstrictive)
side of the ET-1/NO balance.
Interactions
The EDN1 system interacts with the nitric oxide pathway at multiple levels.
Variants in NOS3 (endothelial nitric oxide synthase, rs1799983) that reduce eNOS
activity act in the same vasoconstriction-promoting direction as elevated ET-1.
Carriers of both elevated-ET-1 (rs2070699 T allele) and reduced-eNOS (NOS3) variants
may have compounded vascular tone dysregulation.
rs2070699 is in partial linkage disequilibrium with the functionally important
EDN1 rs5370 (Lys198Asn missense variant, which alters ET-1 receptor binding affinity)
and rs1800543 (promoter variant affecting basal EDN1 transcription). The Foreman 2017
aSAH study genotyped both rs2070699 and the broader EDN1/EDNRA/EDNRB locus,
suggesting haplotype context — not just rs2070699 in isolation — may be the most
informative unit for cerebrovascular risk prediction.
Alla genotyper
Reference genotype — lower endothelin-1 expression and standard vascular tone
You carry two copies of the G allele at rs2070699, the GRCh38 reference genotype. About 29% of people globally share this genotype, with higher prevalence in African populations (approximately 84%) and lower in East Asian populations (approximately 21%). GG carriers show the lowest ET-1 production from this locus in functional studies, supporting more favorable vasodilatory tone. In the PPHN study, the G allele was substantially underrepresented in disease cases relative to controls. No elevated thrombotic, pulmonary hypertensive, or cerebrovascular risk attributable to rs2070699 has been documented for this genotype.
One T allele — moderately elevated endothelin-1 and intermediate vascular risk
You carry one copy of the T allele at rs2070699, the most common genotype globally at approximately 50% of people. Heterozygous GT carriers have intermediate ET-1 expression between the GG and TT genotypes. The T allele is associated with higher circulating ET-1 in functional studies. While most published risk data aggregate across T-allele carriers or focus on TT homozygotes, the intermediate ET-1 elevation in GT carriers is likely to produce a proportionally intermediate vascular effect — modest vasoconstrictor bias and a slightly attenuated nitric oxide response.
Two T alleles — highest endothelin-1 expression and elevated vascular risk
You carry two copies of the T allele at rs2070699, a genotype found in approximately 21% of people globally (higher in East Asian and Latino populations at 29–27%, substantially lower in African populations at under 1%). TT homozygotes show the highest ET-1 production from the EDN1 locus in functional studies. In the PPHN study, TT carriers had ET-1 levels nearly three times higher than GG carriers (3.33 vs 1.22 pg/mL, P=0.002). In the aneurysmal subarachnoid hemorrhage cohort, TT was the only genotype associated with aneurysm rebleeding after hemorrhage. This genotype's elevated ET-1 output creates a persistent vasoconstrictive bias that has implications for pulmonary, cerebrovascular, and systemic vascular health.