rs6841581 — EDNRA

Regulatory variant upstream of the endothelin receptor type A gene that reduces EDNRA transcription, impairing endothelin-1-mediated vasoconstriction and increasing susceptibility to intracranial aneurysm

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EDNRA Upstream Variant — Reduced Endothelin Receptor Expression and Intracranial Aneurysm Risk

The endothelin system is one of the most potent regulators of vascular tone in the human body. Endothelin-1 (ET-1) acts through two receptor subtypes — EDNRA (type A) and EDNRB (type B) — to orchestrate vasoconstriction, vascular smooth muscle proliferation, and arterial wall remodeling. EDNRA is the dominant receptor in vascular smooth muscle and mediates the sustained vasoconstrictive response that maintains cerebrovascular tone11 mediates the sustained vasoconstrictive response that maintains cerebrovascular tone
EDNRA activates Gq-protein signaling, driving IP3-mediated calcium release and PKC activation in smooth muscle cells, producing contraction that can last minutes to hours. rs6841581 sits approximately 900 bp upstream of the EDNRA coding sequence in a region that controls how much receptor protein the cell produces — and one allele makes substantially less of it.

The Mechanism

rs6841581 is a regulatory variant, not a protein-coding change. It lies in the promoter or 5' regulatory region of EDNRA on chromosome 4q31.22 and alters the binding affinity of nuclear transcription factors. Low et al. (2012, Hum Mol Genet) demonstrated that the two alleles of rs6841581 have measurably different affinities for a nuclear protein, and that the susceptible allele drives significantly lower transcriptional activity in luciferase reporter assays22 Low et al. (2012, Hum Mol Genet) demonstrated that the two alleles of rs6841581 have measurably different affinities for a nuclear protein, and that the susceptible allele drives significantly lower transcriptional activity in luciferase reporter assays
Low SK et al. "Genome-wide association study for intracranial aneurysm in the Japanese population identifies three candidate susceptible loci and a functional genetic variant at EDNRA." Human Molecular Genetics, 2012. The result is that carriers of the A allele produce less EDNRA protein per cell.

With fewer functional EDNRA receptors on vascular smooth muscle, the vasoconstrictive response to endothelin-1 is blunted. In cerebral arteries, this impairs the normal maintenance of wall tension and hemodynamic resistance. A heterozygous EDNRA deletion rat model confirmed that reduced EDNRA function is sufficient to trigger intracranial aneurysm formation when combined with hypertensive stress33 A heterozygous EDNRA deletion rat model confirmed that reduced EDNRA function is sufficient to trigger intracranial aneurysm formation when combined with hypertensive stress
Lampmann et al. 2022 (Brain Sci); EDNRA mutant rats showed more extensive aneurysm formation than wild-type controls under equivalent hypertensive conditions. This animal model provides direct causal evidence that the GWAS signal at rs6841581 reflects true EDNRA dysfunction rather than an indirect association.

The Evidence

The original discovery GWAS by Yasuno et al. (2011, PNAS), combining Japanese discovery cohorts with European replication, linked rs6841581 to intracranial aneurysm risk across 5,891 cases and 14,181 controls44 The original discovery GWAS by Yasuno et al. (2011, PNAS), combining Japanese discovery cohorts with European replication, linked rs6841581 to intracranial aneurysm risk across 5,891 cases and 14,181 controls
Yasuno K et al. "Common variant near the endothelin receptor type A (EDNRA) gene is associated with intracranial aneurysm risk." Proc Natl Acad Sci USA, 2011. The association reached genome-wide significance (OR 1.22, P = 2.2 × 10⁻⁸) and held in both East Asian and European populations, making it one of the first trans-ethnic GWAS findings in cerebrovascular genetics.

A meta-analysis of more than 116,000 individuals across 61 studies confirmed rs6841581 as among the most robust genetic risk factors for sporadic intracranial aneurysm (OR 1.22, 95% CI 1.14–1.31)55 A meta-analysis of more than 116,000 individuals across 61 studies confirmed rs6841581 as among the most robust genetic risk factors for sporadic intracranial aneurysm (OR 1.22, 95% CI 1.14–1.31)
Alg VS et al. Neurology, 2013. The consistency of effect across diverse populations and study designs places this association in the strong evidence tier for genetic risk research.

An updated East Asian meta-analysis encompassing 20,609 individuals across 6 populations (Hong et al. 2019, World Neurosurg) refined the estimate to OR 1.244 (95% CI 1.174–1.318, P = 1.36 × 10⁻¹³)66 An updated East Asian meta-analysis encompassing 20,609 individuals across 6 populations (Hong et al. 2019, World Neurosurg) refined the estimate to OR 1.244 (95% CI 1.174–1.318, P = 1.36 × 10⁻¹³)
Hong EP et al. "Association of Endothelin Receptor Type A with Intracranial Aneurysm in 20,609 East Asians.". The A allele frequency is nearly twice as high in East Asian populations (~28%) compared to Europeans (~14%), meaning the absolute genetic attributable risk is greater in East Asian individuals.

Genome-wide pairwise interaction analyses in a Korean cohort identified 11 SNPs showing genome-wide significant interactions with rs6841581, including variants in RYK (a Wnt co-receptor implicated in vascular development) and TNIK (a MAP3K involved in cytoskeletal regulation)77 Genome-wide pairwise interaction analyses in a Korean cohort identified 11 SNPs showing genome-wide significant interactions with rs6841581, including variants in RYK (a Wnt co-receptor implicated in vascular development) and TNIK (a MAP3K involved in cytoskeletal regulation)
Hong EP et al. J Korean Neurosurg Soc, 2023. This interaction architecture suggests that rs6841581's effect on IA risk is amplified by co-occurring variants in vascular developmental pathways.

Practical Actions

Carriers of one or two A alleles at rs6841581 face an incrementally elevated lifetime risk of intracranial aneurysm (unruptured or ruptured as subarachnoid hemorrhage). The per-allele OR of ~1.22–1.24 is modest in absolute terms — population prevalence of unruptured intracranial aneurysms is roughly 2–5% — but the risk is amplifiable by modifiable factors including uncontrolled hypertension and smoking, both of which are potent independent risk factors for aneurysm formation and rupture.

Blood pressure management is the most evidence-supported modifiable lever. The EDNRA pathway mediates ET-1-driven vasoconstriction; reduced EDNRA signaling already impairs vascular wall tension maintenance, and superimposed hypertension exacerbates the hemodynamic stress that triggers aneurysm development. Smoking independently upregulates ET-1 production and promotes vascular inflammation, creating a compounding pro-aneurysm environment for A allele carriers.

MRI angiography (MRA) without contrast can detect unruptured intracranial aneurysms ≥3 mm with high sensitivity and involves no radiation. For A allele carriers with additional risk factors (family history of IA or subarachnoid hemorrhage, hypertension, or smoking history), discussing screening MRA with a neurologist or vascular neurosurgeon is a proportionate response to the genetic finding.

Interactions

rs5335, a 3'UTR variant in the same EDNRA gene, also alters EDNRA expression and is associated with blood pressure variation. Carrying risk alleles at both rs6841581 and rs5335 would be expected to compound the EDNRA downregulation phenotype. The two variants are located at opposite ends of the EDNRA gene (rs6841581 upstream regulatory vs. rs5335 3'UTR) and likely act through independent regulatory mechanisms.

rs6842241, a nearby intergenic variant in the same GWAS locus (Low et al. 2012, OR 1.25), may tag the same functional haplotype as rs6841581 or represent a second independent signal at the EDNRA locus. Both are captured when sequencing this chromosomal region.

rs767603 (LOC105378189) is another intracranial aneurysm susceptibility locus in the heart_inflammation category — the two variants act through independent mechanisms (EDNRA downregulation vs. putative non-coding RNA regulation of vascular wall integrity genes). Both A allele carriers at rs6841581 and T allele carriers at rs767603 benefit from the same blood pressure and smoking avoidance actions.

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal

Common genotype — normal EDNRA expression, standard intracranial aneurysm risk

You carry two copies of the common G allele at rs6841581. This is the reference genotype, present in approximately 71% of people globally. Your EDNRA promoter region has the standard nuclear protein binding affinity, and EDNRA transcriptional output is unaffected by this variant. Your baseline intracranial aneurysm risk from this specific locus is not elevated.

AG Reduced EDNRA Expression Reduced

One copy of the A allele — moderately reduced EDNRA expression and elevated intracranial aneurysm risk

Intracranial aneurysms arise preferentially at arterial bifurcations — locations where hemodynamic shear stress is highest. Normal vascular wall tone, maintained partly by EDNRA-mediated endothelin-1 signaling, helps walls resist this stress-induced remodeling. When EDNRA expression is reduced, even modestly, the wall's adaptive response to pulsatile pressure is compromised.

The OR of ~1.22 per allele translates to approximately a 22% relative risk increase for intracranial aneurysm per A allele. In the context of a 2–3% population prevalence of unruptured aneurysms, a single A allele raises lifetime risk to roughly 2.5–3.5% in the absence of other risk factors. This risk multiplies significantly with hypertension, smoking, or a family history of subarachnoid hemorrhage.

The EDNRA rat model (Lampmann et al. 2022) confirmed that reduced EDNRA function combined with hypertension is sufficient to induce aneurysm formation — neither factor alone was sufficient in most animals. This gene-environment interaction supports prioritizing blood pressure control as the highest-value intervention for A allele carriers.

AA Impaired EDNRA Expression Decreased

Two copies of the A allele — substantially reduced EDNRA expression and the highest aneurysm risk from this variant

In the AA homozygous state, both regulatory copies carry the low-transcriptional- activity allele identified by Low et al. (2012). The functional consequence — reduced EDNRA density on vascular smooth muscle — is at its maximum for this locus. The endothelin pathway mediates not only acute vasoconstriction but also long-term vascular smooth muscle maintenance. Chronic underactivation through reduced receptor density impairs the wall's ability to remodel adaptively in response to pulsatile shear stress, particularly at cerebral arterial bifurcations.

The rat model (Lampmann et al. 2022) showed that even heterozygous EDNRA deletion — analogous to the AG genotype — was sufficient to trigger aneurysm formation under hypertensive conditions. The AA state represents a more severe receptor deficit, and the combination of AA genotype with any additional vascular risk factor (hypertension, smoking, stimulant use, hypercholesterolemia) merits active clinical attention.

The interaction analysis (Hong et al. 2023) identified 11 SNPs that interact with rs6841581 at genome-wide significance, including RYK (Wnt co-receptor in vascular development) and TNIK (cytoskeletal MAP3K). AA carriers who also carry risk variants in these interacting loci may face substantially higher absolute risk than the EDNRA signal alone predicts. Genome-wide interaction effects are not yet incorporated into standard clinical risk calculators.