rs5335 — EDNRA

EDNRA 3'UTR — Endothelin Receptor Variation and Blood Pressure Regulation

Endothelin-1 (ET-1) is one of the most potent vasoconstrictors in human physiology, acting through two receptor subtypes to control vascular tone, blood pressure, and cardiac remodeling. The endothelin receptor type A¹¹ endothelin receptor type A
EDNRA is a G protein-coupled receptor that mediates ET-1's vasoconstriction, smooth muscle proliferation, and aldosterone release effects binds ET-1 with high affinity on vascular smooth muscle cells, arterial walls, and cardiac tissue, triggering sustained vasoconstriction. The rs5335 variant sits in the 3' untranslated region (3'UTR)²² 3' untranslated region (3'UTR)
The 3'UTR is the section of mRNA after the protein coding sequence; it contains regulatory elements that govern mRNA stability, translation efficiency, and response to microRNAs of EDNRA, where it can influence how much receptor protein is produced without altering the receptor's amino acid sequence.

The Mechanism

The rs5335 G>C change at chromosome 4:147,542,688 (GRCh38) falls within the 3'UTR of the EDNRA gene transcript. Variants in this regulatory region can alter the binding affinity of microRNAs and RNA-binding proteins, changing the stability and translation efficiency of EDNRA mRNA. Evidence from Darrah et al. 2010³³ Darrah et al. 2010
EDNRA variants associate with smooth muscle mRNA levels, cell proliferation rates, and cystic fibrosis pulmonary disease severity. Physiological Genomics. 2010 demonstrated that EDNRA polymorphisms, including rs5335, directly associate with EDNRA mRNA levels in smooth muscle cells and with differences in smooth muscle cell proliferation rates — establishing a direct molecular mechanism by which this 3'UTR variant influences vascular biology.

Higher EDNRA receptor expression on vascular smooth muscle cells increases sensitivity to circulating ET-1. Since ET-1 signaling through EDNRA drives sustained vasoconstriction and promotes vascular smooth muscle hypertrophy, genetically elevated EDNRA expression translates to higher vascular resistance and blood pressure. This mechanism is consistent with the clinical observations linking GG genotype to elevated diastolic blood pressure.

The Evidence

The foundational cardiovascular study for rs5335 was Rahman et al. 2008⁴⁴ Rahman et al. 2008
Common genetic variation in the type A endothelin-1 receptor is associated with ambulatory blood pressure: a family study. Journal of Human Hypertension. 2008, which established that naturally occurring genetic variation in EDNRA is associated with ambulatory blood pressure measurements in a family cohort — a study design that controls for shared environmental influences.

More directly, Zeng et al. 2019⁵⁵ Zeng et al. 2019
Associations of EDNRA and EDNRB Polymorphisms with Intracerebral Hemorrhage. World Neurosurgery. 2019 found that GG genotype carriers had significantly higher diastolic blood pressure than CG or CC carriers in intracerebral hemorrhage patients (91.69 vs 84.71 mmHg, p=0.004). This 7 mmHg difference in diastolic pressure is clinically meaningful — chronic diastolic hypertension is a major modifiable risk factor for stroke, heart failure, and renal disease.

Downstream cardiovascular consequences have been documented in multiple outcome studies. Ellis et al. 2012⁶⁶ Ellis et al. 2012
Association between endothelin type A receptor haplotypes and mortality in coronary heart disease. Personalized Medicine. 2012 found EDNRA haplotypes involving rs5335 associated with mortality differences in coronary heart disease patients. Zhang and Sui 2014⁷⁷ Zhang and Sui 2014
Effect of SNP polymorphisms of EDN1, EDNRA, and EDNRB gene on ischemic stroke. Cell Biochemistry and Biophysics. 2014 extended the association to ischemic stroke risk. Griessenauer et al. 2018⁸⁸ Griessenauer et al. 2018
Associations between endothelin polymorphisms and aneurysmal subarachnoid hemorrhage. Journal of Neurosurgery. 2018 linked EDNRA variants to aneurysmal subarachnoid hemorrhage outcomes, vasospasm, and delayed cerebral ischemia — conditions where ET-1-mediated vasoconstriction plays a central pathological role.

In oncology pharmacogenomics, Kopeva et al. 2022⁹⁹ Kopeva et al. 2022
Anthracycline-induced cardiotoxicity in women without cardiovascular diseases. Acta Cardiologica. 2022 identified rs5335 as a molecular predictor of cardiotoxicity from anthracycline chemotherapy (drugs like doxorubicin), suggesting that EDNRA genotype influences how the heart responds to chemotherapy-induced endothelial stress.

Practical Implications

Your rs5335 genotype relates to how sensitively your vasculature responds to endothelin-1 signaling. GG homozygotes — who show elevated EDNRA expression and higher diastolic BP — benefit from earlier and more targeted blood pressure monitoring, particularly diastolic pressure tracking, and benefit more from interventions that modulate the endothelin pathway. Endothelin receptor antagonists (bosentan, ambrisentan, macitentan) are approved drugs for pulmonary arterial hypertension that directly target EDNRA; your genotype may influence response to these agents.

Dietary nitrates (beetroot juice, leafy greens) and supplemental L-arginine support nitric oxide production in endothelial cells, partially counterbalancing ET-1-driven vasoconstriction. Magnesium is a natural calcium antagonist that reduces vascular smooth muscle responsiveness to vasoconstrictors including ET-1. Regular aerobic exercise downregulates endothelin sensitivity over time through shear-stress-mediated increases in eNOS expression.

Interactions

The endothelin signaling system involves both EDNRA and EDNRB receptors, which have opposing vascular effects: EDNRA drives vasoconstriction while EDNRB on endothelial cells promotes vasodilation via nitric oxide. The Zeng 2019 study examined both rs5335 (EDNRA) and EDNRB polymorphisms together. Variants in EDN1 (rs5370, Lys198Asn) affect circulating ET-1 levels and would interact with EDNRA receptor sensitivity variants — individuals with both elevated ET-1 production (EDN1 Lys198Asn) and increased EDNRA receptor sensitivity (rs5335 GG) may face compounded vasoconstriction drive.

The EDNRA rs5335 G allele also shows strong population stratification: it is common in Europeans (~60%) but rare in Africans (~27%), meaning population-specific haplotype contexts may modulate the blood pressure effect direction and magnitude.