A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression

Gupta, Rajat M.; Hadaya, Joseph; Trehan, Aditi; Zekavat, Seyedeh M.; Roselli, Carolina; Klarin, Derek; Emdin, Connor A.; Hilvering, Catharina R.E.; Bianchi, Valerio; Mueller, Christian; Khera, Amit V.; Ryan, Russell J.H.; Engreitz, Jesse M.; Issner, Robbyn; Shoresh, Noam; Epstein, Charles B.; Laat, Wouter de; Brown, J.; Schnabel, Renate B.; Bernstein, B; Kathiresan, Sekar

doi:10.1016/j.cell.2017.06.049

Cited by 381 publications

(342 citation statements)

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“…Gupta et al[20] demonstrate that the cis-regulatory action of the G allele at rs9349379 is associated with higher EDN1 expression and higher ET-1 secreted peptide, and that the G allele at rs9349379 is associated with increased risk of coronary artery disease but lower risk of migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Of these conditions, coronary artery disease has an atherogenic basis and a vasoconstrictor component.…”

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confidence: 99%

“…Recently, Gupta et al[20] published an interesting paper suggesting that a genetic variant associated with 5 vascular diseases is a distal regulator of ET-1 gene ( EDN1 ) expression. Genome-wide association studies have implicated the PHACTR1 locus (6p24) in the risk associated with 5 vascular diseases: coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension.…”

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confidence: 99%

“…Gupta et al [20] pointed out the association of the rs9349379 variant with lower risk of hypertension. How can we understand this?…”

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confidence: 99%

“…Genome-wide association studies have implicated the PHACTR1 locus (6p24) in the risk associated with 5 vascular diseases: coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. By performing genetic fine mapping, Gupta et al[20] examined a common single nucleotide polymorphism (SNP) in the third intron of the PHACTR1 gene, rs9349379, as the potential variant responsible for the association. Using epigenomic data from human tissue, they characterized an enhancer at rs9349379 exclusively in aorta, which suggested that this SNP could have a regulatory function on the vasculature.…”

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confidence: 99%

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Does Endothelin-1 Raise or Lower Blood Pressure in Humans?

Schiffrin¹

2018

Nephron

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Subject of Review: Gupta et al. [Cell 2017; 170: 522–533] have shown that a genetic variant associated with the 5 vascular diseases is a distal regulator of endothelin (ET)-1 gene (EDN1) expression. A common single nucleotide polymorphism (SNP) in the third intron of the PHACTR1 gene, rs9349379, is the potential variant responsible for increased risk of coronary artery disease, and lower risk of migraine, carotid dissection, fibromuscular dysplasia, and hypertension. Since ET-1 acts through ET type B receptors (ET_BR) on endothelial cells to stimulate the production of nitric oxide and prostacyclin and induce vasodilation, this may contribute to these findings. Second Opinion: However, ET-1 has been demonstrated to play a role in experimental and human hypertension. How can enhanced transcription of EDN1 and translation leading to increased production of ET-1 by endothelial cells play a role in hypertension despite the availability of data that suggest a hypotensive action of ET-1? This could depend on the genetic background of individuals. In some humans, the increased ET-1 vasoconstrictor action on ET_AR and ET_BR in vascular smooth muscle might predominate over the vasodilator effects exerted via endothelial ET_BR, thus resulting in elevated blood pressure. Conclusion: Alternatively, hypertension could be attributed to renal actions of ET-1. Either of these pathophysiological actions may explain a hypertensive role of ET-1 despite a lower risk of hypertension associated with the G allele at rs9349379, the common SNP in the PHACTR1 gene that is a distal regulator of EDN1 and leads to an increased expression of ET-1.

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confidence: 99%

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confidence: 99%

“…Gupta et al [20] pointed out the association of the rs9349379 variant with lower risk of hypertension. How can we understand this?…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Does Endothelin-1 Raise or Lower Blood Pressure in Humans?

Schiffrin¹

2018

Nephron

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“…These findings are supported by clinical and preclinical studies that suggest a direct role of the ET A receptor on the development of atherosclerosis 57, 58, 59, 60, 61. Recently, Gupta and colleagues demonstrated in a separate genome‐wide association study project that a single‐nucleotide polymorphism common in 5 vascular diseases, including coronary artery disease, promotes exaggerated endothelium‐derived ET‐1 and higher plasma ET‐1 62. It would be interesting to determine whether ET A receptor and ET‐1 single‐nucleotide polymorphisms are coincident in vascular disease.…”

Section: Discussionmentioning

confidence: 83%

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

Fox

Becker

Loria

et al. 2018

JAHA

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BackgroundAcute psychosocial stress provokes increases in circulating endothelin‐1 (ET‐1) levels in humans and animal models. However, key questions about the physiological function and cellular source of stress‐induced ET‐1 remain unanswered. We hypothesized that endothelium‐derived ET‐1 contributes to the acute pressor response to stress via activation of the endothelin A receptor.Methods and ResultsAdult male vascular endothelium‐specific ET‐1 knockout mice and control mice that were homozygous for the floxed allele were exposed to acute psychosocial stress in the form of cage switch stress (CSS), with blood pressure measured by telemetry. An acute pressor response was elicited by CSS in both genotypes; however, this response was significantly blunted in vascular endothelium‐specific ET‐1 knockout mice compared with control mice that were homozygous for the floxed allele. In mice pretreated for 3 days with the endothelin A antagonist, ABT‐627, or the dual endothelin A/B receptor antagonist, A‐182086, the pressor response to CSS was similar between genotypes. CSS significantly increased plasma ET‐1 levels in control mice that were homozygous for the floxed allele. CSS failed to elicit an increase in plasma ET‐1 in vascular endothelium‐specific ET‐1 knockout mice. Telemetry frequency domain analyses suggested similar autonomic responses to stress between genotypes, and isolated resistance arteries demonstrated similar sensitivity to α1‐adrenergic receptor‐mediated vasoconstriction.ConclusionsThese findings specify that acute stress‐induced activation of endothelium‐derived ET‐1 and subsequent endothelin A receptor activation is a novel mediator of the blood pressure response to acute psychosocial stress.

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Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection

et al. 2020

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IMPORTANCE Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death.OBJECTIVE To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility. DESIGN, SETTING, AND PARTICIPANTSThis single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD

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A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression

Cited by 381 publications

References 71 publications

Does Endothelin-1 Raise or Lower Blood Pressure in Humans?

Does Endothelin-1 Raise or Lower Blood Pressure in Humans?

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection

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