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Current Clinical Pharmacology, 2016, 11, 191-210 191

REVIEW ARTICLE

Polymorphism in Endothelin-1 Gene: An Overview

Musa Ahmed1,3,* and Abir Rghigh2

1
Faculty of Pharmacy, University of Benghazi, Benghazi, Libya; 2Faculty of Pharmacy, University of Tripoli, Tripoli,
Libya; 3Present Address: Vroom Street #1, Jersey City, NJ 07306, USA

Abstract: Endothelin-1, (ET-1, EDN1) is an endogenous polypeptide which

A R T I C L E H I S T O R Y
 
Received: December 10, 2015
Revised: June 12, 2016
Accepted: June 15, 2016
DOI:
10.2174/15748847116661607010009
00
Keywords: Endothelin, endothelin-1(ET-1), polymorphism, rs5370.
demonstrates dominant vasoconstriction activity and mitogenic effect. It has positive
inotropic and chronotropic effects on the heart, stimulates the sympathetic and the
renin-angiotensin-aldosterone systems and modifies homeostasis. The human ET-1
gene which consists of 6836 nucleotides located on chromosome 6p23-p24 produces
Pre-pro-ET-1, which is consequently cleaved to big-ET-1. The mature 21-amino acid
ET-1 is generated by subsequent enzymatic cleavage of the big-ET-1. A comprehensive
review of the literature on the consequences of different ET-1 gene variants on ET-1
linked diseases has not been accomplished. Many variants of ET-1 gene, including
Musa Ahmed
transversion, transition, insertion, and repeated nucleotide polymorphisms, which
influence the hereditary risk of cardiovascular and other related diseases have already been located,
genotyped, and examined. Among them ten polymorphisms including transversion; -1370 (T-1370G)
(rs1800541), +5665 (Lys198Asn) (rs5370), G2288T polymorphisms (rs2070699), and -974 C>A
(rs3087459) polymorphism, transition; +3660 (Glu106Glu) (rs5369), G(8002)A (rs2071942), rs1476046
polymorphism , rs2071943 polymorphism, and rs9296345 polymorphism, and insertion/delete; +138
(+138/ex1ins/delA) (rs1800997) were studied and phenotyped extensively. Some significant associations
with many different diseases (phenotypes) especially those related to cardiovascular system diseases such
as hypertension, ischemic diseases, angina, and acute coronary syndrome have been described in the
literature. Some are associated with other diseases such as asthma, pulmonary edema, hearing
impairment, obesity and sleep apnea. Moreover, some are modifying the course and adverse effects of
several drugs. Many of these polymorphisms were studied, thus some inner complex association manner
was also described.

INTRODUCTION
Endothelin
In 1985, Hickey et al. [1] discovered a vasoconstrictor
peptide in a culture media of bovine aortic endothelial cells
[1]. Four years later, in 1988, Yanagisawa et al. [2] isolated
and correctly predicted the structure of this endothelium-
derived constricting factor from the supernatant of porcine
aortic endothelial cells named endothelin (now called
endothelin-1 or ET-1). Yanagisawa also predicted the
biosynthesis of the mature 21-amino acid peptide (ET-1) by
proteolytic cleavage at paired basic residues of a 39-amino
acid intermediate "Big Endothelin" which came from
cleavage of a large protein named proendothelin [2].
In the same year, another family of peptides with high
similarity to ET-1 was discovered in the venom of a snake
Atractaspis and named sarafotoxins. In vivo, this family
causes similar vasoconstriction effects of ET-1 enough to
*Address correspondence to this author at the Faculty of Pharmacy,
University of Benghazi, Benghazi, Libya; Tel: +13475240175 or 9292455170);
Fax; +1 7186041400; E-mail: mabuajila@yahoo.ca
contract the coronary arteries and causes the heart to stop
[3, 4].
“Endothelin” refers to a family of 21-amino acid peptides
existing in nature in four different isoforms, endothelin-
1(EDN1 also ET-1), endothelin-2 (EDN2, ET-2), endothelin-
3 (EDN3, ET-3) and endothelin β or mouse vasoactive
intestinal contractor (VIC). The endothelin isoforms have a
significant structural resemblance, including two disulfide
bonds one of them is between Cys 3 and Cys 11, and the
other one is between Cys 1 and Cys 15, a hydrophobic C-
terminus (residues 16-21) and a collection of polar charged
side chains on the hairpin loop. The differences between
these isoforms are mainly in some amino acid units; for
instance, the difference between ET-1 and ET-1 is in the
amino acid tryptophan (Trp) and leucine (Leu) (number 6
and 7) in endothelin-2 instead of leucine (Leu) and
methionine (Met) in ET-1. The primary isoform in the
human cardiovascular system is ET-1, which is the most
abundant and the most potent vasoconstrictor discovered to
date. It is more powerful than angiotensin II by tenfold, with
extremely long duration of pressor effects [2, 5, 6]. Dual
secretory pathways contribute to govern the ET-1 release and

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192 Current Clinical Pharmacology, 2016, Vol. 11, No. 3
level in circulation [6]. The constitutive pathway, which is to
maintain the endogenous vascular tone by producing durable
constriction of the vascular smooth muscle [7], the other way
is by releasing ET-1 from Weibel-Palade bodies (the
endothelial cell- specific storage granules) after stimulation
by external physiological stimulators [6].
Endothelin Receptors
Two main endothelin (ET) receptor subtypes, termed
endothelin receptor subtype A (ETA) and endothelin receptor
subtype B (ETB), were identified [8-14]. The assembly of the
mature receptors belongs to the seven-transmembrane (7TM)
domain, G protein-coupled rhodopsin- type receptor
superfamily, characterized by seven stretches of 20 to 27
hydrophobic residues. Two distinct ligand binding
subdomains were predicted in each endothelin receptor. The
selectivity is largely determined by the extracellular loops
located in transmembrane (TM) 4 to 6 [15-17]. Only 59%
similarity was displayed between the two endothelin
receptors [15]. Other receptors were found in other mammals
such as a dual angiotensin II/ET-1 receptor in rats, a different
ETB receptor in birds, and an ETC receptor selective for ET-3
in frogs [18].
Endothelin receptor is a perfect model for the study of
the function of the heptahelical G-protein-coupled receptor
[19]. The ETA receptor subtype is well known to mediate
vasoconstrictor activity and is widely localized in vascular
smooth muscle of cardiovascular tissues [12-14, 20-23],
central nervous system [24], retina [25], and placenta [26].
The ETB receptor is commonly localized in many types of
tissues such as the brain, vascular smooth muscle (VSM),
lung, kidney, heart [10, 27-29] retina [25], and placenta [26].
While kidney cortex and medulla contain both receptors;
ETA and ETB [30]. Many researchers think that the ETB
receptor is linked with vasodilator activity only [15-21],
partially due to the release of the endothelium-derived
relaxing factor (EDAF). However, several reports have
revealed that ETB receptor also facilitates vasoconstriction in
particular tissues and species [16, 17, 20-23, 27-29, 31, 32].
Endothelin receptors, ETA and ETB can be antagonized
competitively with a variety of selectivity [33-52], while the
allosteric antagonism was reported only for ETA receptors
[53- 55].
Activation of ETA receptors triggers phospholipase C
pathway, which leads to long-lasting vasoconstriction due to
the buildup of inositol triphosphate and intracellular calcium.
In other tissues, ETA receptors stimulate cell proliferation
[18].
Activation of ETB receptors kindles the release of
prostacyclin and NO, promotes the reuptake of ET-1 by
endothelial cells and removes the circulating ET-1 in
pulmonary tissues. Moreover, it prevents apoptosis and
restricts endothelin converting enzyme-1 (ECE-1) expression
in endothelial cells [18].
Pathological and Physiological Role of Endothelin-1
(ET-1)
Among the endothelin peptide family (ET-1, ET-2, and
ET-3), the primary isoform in the vascular system is ET-1. In
Ahmed and Rghigh
the cardiovascular system, ET-1 has a vital role of the potent
vasoconstriction ability; it provokes the renin-angiotensin-
aldosterone, and stimulates the sympathetic nervous systems.
It demonstrates positive inotropic and chronotropic effects
on the heart and also has mitogenic properties, and affects
homeostasis [56].
ET-1 possibly acts in two ways. Firstly, it performs as a
locally active paracrine factor; the other action is a
circulating hormone to regulate the tone of arteries and veins
[57-59]. The overall cardiac function of ET-1 is hard to
evaluate in vivo, although it demonstrates potent inotropic
action in vitro. ET-1 reduces the cardiac output when
systemically infused in either heart failure patients or healthy
persons. This effect is possibly due to the peripheral and
coronary vasoconstriction, but not attributed to the negative
inotropic effect of ET-1 on the heart [60]. ET-1 has no effect
on heart failure patients, in contrast with its inotropic effect
on healthy subjects. ET-1 may amplify the action of other
vasoconstrictor and neuroendocrine systems in normal and
disease conditions. ET-1 seems to enhance plasma renin
activity, augment adrenaline, and aldosterone biosynthesis
and boost angiotensin II turnover. On the other hand, some
vasoconstrictors and neuroendocrine systems amplify or
stimulate ET-1 secretion in vitro and rise tissue and
circulating ET-1 and ECE levels in vivo such as angiotensin
II. Moreover, some reports indicated that ET-1 might
amplify other vasoconstrictors reflexes leading to vast
pathophysiological consequence even at low plasma
concentrations. This conclusion came from the potentiation
of contractile responses of human arteries in response to
catecholamines and serotonin by the addition of sub-
threshold concentrations of ET-1 [61-64]. ET-1 is thought to
have a pro-arrhythmogenic effect and a pathophysiological
role in the progression of ischemia /reperfusion and
myocardial and vascular remodeling based on its ability to
stimulate vascular smooth muscle proliferation and cardiac
hypertrophy [65].
Mild and chronic overproduction of ET-1 has no impact
on blood pressure, as demonstrated by overexpressing
endothelin gene transgenic mice (ET-1) [66] and rats (ET-2)
[67]. Reports assumed that long-term activation of the
paracrine endothelin system triggers counter-regulating
mechanisms, such as downregulation of endothelin receptors
or interference with post-receptor signal transduction
pathways or by activation of other mediators such as the NO
system. However, other clinical manifestations such as low
body weight, diminished fur density, kidney interstitial
fibrosis, renal cysts, glomerulosclerosis and narrowing of
arterioles, decreased creatinine clearance, elevated urinary
protein excretion and salt-dependent hypertension occurred.
These effects are explained by the paracrine action of ET-1
and ET-2 in the kidney [66-68].
The overproduction of ET-1 stimulates ETB receptor to
mediate NO synthesis leads via cGMP to a decreased
synthesis of prepro–ET-1 mRNA [66-68]. This negative
feedback mechanism of NO on prepro–ET-1 mRNA may
explain the rather low ET-1 overexpression seen in ET-1
transgenic mice [66-68]. The release of NO causes
vasodilation primarily by increasing intracellular cGMP
levels. Moreover, it inhibits ET-1 action and release from
Polymorphism in Endothelin-1 Gene: An Overview
epithelial cells [69]. Block of NO action leads to
vasoconstriction response and hypertension attributed to
ET-1 activity [69]. The vasoconstriction and hypertension
diminished by using ET-1 receptors blockers in acute NOS
blockade models [69]. In chronic models, hypertension has
not been found to be reversed by ET-1 antagonism due to
cardiovascular system compensatory changes [69].
ET-1 is believed to play a significant role in the
development of chronic heart failure and injury process [57,
58]. This potent vasoconstrictor peptide also reveals a vital
role in several other cardiovascular illnesses [5, 16, 18, 20].
These are hypertension [59-63], coronary vasospasm [64]
unstable angina [65], myocardial infarction [70], cardiac
insufficiency [71], atherosclerosis [72, 73], and cerebral
vasospasm associated with subarachnoid haemorrhage [74].
ET-1 also plays role in other related diseases and patho-
physiological status like Raynaud's disease [75], migraine
[76, 77], inflammatory pain and cutaneous inflammation
[78], platelet aggregation [79], diabetes and obesity [80-83],
autoimmune diseases and transplantation rejection [84],
tumour cell proliferation and invasion [85]. Also, ET-1 has a
role in the pathophysiology of the placenta [86-88], lung
diseases [89], and renal hemodynamic and renal diseases
[84], (Fig. 1).
Biosynthesis of Endothelins
Endothelin isopeptides encoded by a distinct gene
predicted amino acid sequences for preproETs are large
peptides (~200 amino acids) with particular species and
isopeptides differences. The expression of this gene induced
by many stimuli such as mechanical and shear stress,
oxidized lipoproteins, hypoxia, lipopolysaccharide, and high
levels of glucose, and inhibited by NO, prostacyclin, atrial
natriuretic peptide, and epidermal growth factor [135].
Pre-pro-ET-1 gene, ET-1 gene, has cytogenetic location:
chr6: p24.1 - p24.1, and size of 105 base pair (bp) and
contains 5 exons and 4 introns [136]. Pre-pro-ET-1 mRNA
consists of 2026 nucleotides produced by transcription of the
human ET-1 gene that consists of 6836 nucleotides [137].
The large peptide ‘preproET-1’ (202- 212-amino acid) [5,
138] is cleaved at two typical dibasic processing sites by
dibasic pair-specific furin-like protease [69] to generate 38-
40 amino acid polypeptide known as big-endothelin (B-ET).
Fig. (1). Pathological and physiological role of endothelin-1.
Current Clinical Pharmacology, 2016, Vol. 11, No. 3 193
B-ETs undergo a proteolytic cleavage, in the endothelial
cells, at the unusual processing site, Trp21-Val22, by a
putative endothelin converting enzyme (ECE) to give mature
ETs (The mature 21-amino acid ET-1) and the corresponding
C-terminal fragments (CTF) [5]. ECE belongs to a subgroup
of zinc metalloproteinases from the neprilysin superfamily
operating under usual physiological conditions and consists
of two isoforms ECE-1 (at pH 7.0) and ECE-2 (at pH 5.5)
[69, 139, 140]. A third ECE enzyme is ECE-3, which has
specificity for big ET-3 and separated from bovine iris
microsomes [141]. To date, four isoforms of the ECE-1
enzyme have been recognized in humans, namely ECE-1a–d
[142, 143]. These isoforms differ in their location inside or at
the surface of the endothelial cell and maintain the equal
efficiency of conversion of Big ET-1 to ET-1 [144].
Studies indicate considerable levels of the ET-1 peptide
in ECE knockout mice [145]. This led to the discovery of
non-ECE pathways by which big-ET-1 is converted into
ET-1. One of these ways is by mast cell chymase (mast cell-
derived serine protease) [146, 147] producing ET-1 (1-31),
which is a constrictor of both tracheal and vascular smooth
muscle raising the possibility of the contribution of ET-1 in
allergic inflammation and asthma [146, 148]. Another way is
by a neutral endopeptidase (NEP) which works in human
bronchial smooth muscle cells and has a pivotal role in the
conversion of ET-1 (1–31) to ET-1 [146, 149].
More recently, other matrix metalloproteinases (MMPs),
such as gelatinase, MMP-2, and MMP-9 are reported to
generate another active ET-1 peptide of 32 amino acids
in length (ET-1(1–32) which demonstrate comparable
vasoconstriction activity in on rat mesenteric arteries [139,
140], (Fig. 2).
Endothelin-1 Gene Polymorphism
The alteration in DNA sequence between populations and
individuals is defined as genetic polymorphism; this
difference might give rise to different phenotypes. The
causes of polymorphism could be sequence repeats, insertions,
deletions, single nucleotide polymorphisms (SNPs), and
recombination. The majority of genetic variations among
people are single nucleotide polymorphisms (SNP) which
are mutations that arise at single nucleotide positions. The
single nucleotide polymorphisms (SNP) are the majority of
194 Current Clinical Pharmacology, 2016, Vol. 11, No. 3 Ahmed and Rghigh

Fig. (2). Transcription and maturation of ET-1.

genetic variations among people which are mutations that
appear at single nucleotide positions. More than 7 million
single nucleotide polymorphisms were estimated in the
human genome [150]. An individual gene such as the ET-1
gene can associate with hundreds of SNP’s. By reviewing
SNP’s and other polymorphism forms, the proposed
overview determines the manner and extent of genetic
variations within ET-1 gene. This information could be used
as a tool to indicate higher risk patients at any of the linked
cardiovascular diseases or other ET-1 associating illnesses,
and subsequent worse outcomes, also, it can be used to
modify the treatment procedures and doses.
The actual build number 312 of the SNPs database
contains 252 active SNPs in the genomic region of the
human ET-1 gene. Examples of transversion, transition and
insertions/deletions polymorphisms in the ET-1 gene are
listed in Table 1.
Among these polymorphisms, ten variants of ET-1 gene
and their associated diseases (phenotypes) were studied
extensively in the literature including; transversion, T/G
transversion at position -1370 (T-1370G) (rs1800541), G/T
transversion in exon 5 at position +5665 (codon 198;
Lys198Asn) (rs5370), G2288T polymorphisms (rs2070699)
[152] -974 C>A (rs3087459) polymorphism [151], transition,

Table 1. Examples of transversion, transition and insertions/deletions polymorphisms in EDN1 gene.

Transversion - T/A transversion occurs at -1398, and exists in association with the G/A transition located at -1396 (T-1398A, G-1396A) [56].
- T/G transversion occurs at -1370 (T-1370G) (rs1800541) [56].
- G/T transversion occurs in exon 5 located at +5665 (codon 198; Lys198Asn) (rs5370) [56].
- T/G transversion occurs in intron 2 located at +2176 (T+30/in2G) [56].
- G2288T Polymorphisms (rs2070699) [56].
- 974 C>A (rs3087459) polymorphism [151].

Transition - G/A transition occurs in intron 1 located at +1932 (G-46/in1A) [56].

- T/C transition occurs in intron 2 located at +3539 (T-37/in2C) [56].
- G/A transition occurs in exon 3 located at +3660 (codon 106), this polymorphism causes a synonymous change (Glu106Glu)
(rs5369) [56].
- G/A transition occurs in intron 4 located at +4395 (G+356/in4A) [56].
- T/C transition occurs in the 3'-untranslated region in exon 5 located at +6438 (T+834/ex5C) [56].
- T/C transition occurs in the 3'-untranslated region in exon 5 located at +76485 (T+881/ex5C) [56].
- G(8002)A polymorphism in intron 4 (rs2071942) [152].
- G/A transition (rs1476046) polymorphism [153].
- G/A transition (rs2071943) polymorphism [154].
- C/T transition (rs9296345) polymorphism [155].

Insertion/Deletion -Insertion T occurs in intron 4 located at +5567 (-38/in4ins/delT) [56].

-Insertion A occurs in the 5'-untranslated region in exon 1 located at +138 (+138/ex1ins/delA) (rs1800997) [56].
Polymorphism in Endothelin-1 Gene: An Overview
Fig. (3). Polymorphisms of ET-1 gene.
G/A transition in exon 3 at position +3660 (codon 106)
(Glu106Glu) (rs5369), G(8002)A polymorphism in intron 4
(rs2071942) [152], G/A transition rs1476046 polymorphism
[153], G/A transition rs2071943 polymorphism [154], and
C/T transition rs9296345 polymorphism [155], insertion/
delete, insertion A in the 5'-untranslated region (exon 1)
at position +138 (+138/ex1ins/delA) (rs1800997) [56], the
heritable risk of many cardiovascular illnesses, such as
hypertension, coronary heart disease, ventricular arrhythmia,
and other related diseases can be largely affected by these
polymorphisms, therefore, the aim of this overview is to
enlighten these polymorphisms in more detail (Fig. 3).
PHENOTYPED ET-1 GENE POLYMORPHISMS
Rs5370; G/T Transversion in Exon 5 Position +5665
(Codon 198; Lys198Asn or K198N)
The rs5370 is the polymorphism of preproendothelin-1
which affects the vascular tone [156]. This polymorphism
occurs when purine (G- Guanine) is substituted by a
pyrimidine (T-Thymine) in the DNA sequence (point
mutation) and defined as a G- to-T transversion at location
5665 affecting the 61st nucleotide of exon 5, position; Chr.6:
12296255. The consequence of this specific alteration in the
preproendothelin-1 gene is the variation of the mature
protein structure. In this situation, the substitution of
Guanine with Thymine led to the introduction of asparagine
(Asn) in place of lysine (Lys) at codon 198, leading to
different preproendothelin-1 isoforms with different
structures and biological activities, thereby leading to
different biological ET-1 isoforms. The genotypes of this
polymorphism are wild type: GG, heterozygous: GT, and
homozygous: TT. The occurrence of T allele at Codon 198
in maternal ET-1 is linked with higher ET-1 levels in
circulation which is correlated with the severity of
hypertension in preeclampsia [157]. This allele also
Current Clinical Pharmacology, 2016, Vol. 11, No. 3 195
displayed increased responsiveness to ET-1 and angiotensin
II in various tissues containing ET-receptors such as human
mammary artery ring segments, probably in relation with
higher calcium sensitivity [156]. The incidence of the
Lys198Asn polymorphism is not provided in enormous
population study or for particular ethnic groups. However,
many studies investigate the occurrence of this allele among
the patient and control groups of many diseases [157-160].
For instance, in a sample of 400 high blood pressure
individuals and 150 normotensives, the prevalence of T
allele in normotensive individuals was found to be 57.3%
(GG), 41.3% (GT), and 1.43% (TT), while in hypertensive
patients the prevalence was 54.75% (GG), 43% (GT) and
2.25% (TT) [158].
The T allele of rs5370 polymorphism alone [161] or with
(+138 A; rs10478694) 3A/4A genotype increases the
individual's susceptibility to the idiopathic pulmonary arterial
hypertension (IPAH) that affects its course of progression
[162]. In Japanese population, the T allele seems to work
interactively with serotonin 2A receptor polymorphism
5-HT2A T102C, a neurotransmitter and vasoconstrictor agent
implicated in blood pressure disease, to induce hypertension
[163].
In stress condition, T allele individuals displayed greater
diastolic blood pressure than others [136]. Carriers of this
allele also demonstrate high resting blood pressure (BP)
levels among overweight middle-aged adults [164].
T allele carriers are at risk of developing arterial
hypertension in Kazakh people ethnic group [165], and in
pregnant women [166]. Other reports linked this allele to
hypertension coupled with obesity [167-169]. Hypertensive
patients, with three-vessel disease, carrying TT homozygous
genotype seem at high risk to develop coronary artery
disease (CAD). Therefore, this polymorphism could be used
196 Current Clinical Pharmacology, 2016, Vol. 11, No. 3
as a tool to distinguish high-risk subgroups among various
populations of hypertensive individuals [158]. T allele
individuals also have more predisposition for heart failure
(HF) disease than G allele carriers [170].
Although previous reports connecting this polymorphism
with hypertension, Wiltshire et al. [171] found no sufficient
data supporting the association between K198N
polymorphism with high blood pressure, systolic blood
pressure, lipid levels and insulin resistance or metabolic
syndrome [171].
In one study, essential hypertension and hypertension
response to stress stimulation was linked to unproductive
anger expression. TT Carriers with poor anger control skills
exhibited the greatest total peripheral resistance index
(TPRI) reactivity. People with a genetic tendency for
exaggerated vasoconstriction who also show weak anger
control skills are more susceptible to develop stress- induced
essential hypertension [173]. Some studies also reveal that T
carriers have more tendencies to obesity [168], and have
more tendencies to hearing impairment and loss among old
and middle-aged Japanese than carriers of GG homozygous
(wild-type) [174]. T allele individuals are at greater risk of
sudden sensorineural hearing loss (SSNHL) than G allele.
However, G allele carriers manifest complicated form of the
disease [175]. In Chinese Han population in northern China
(males and females), eight polymorphisms suspected to affect
the ischemic stroke (IS); SNPs (rs1800541, rs2070699, and
rs5370 in ET-1 gene; rs1801708, rs5333, and rs5335 in ETA
gene; and rs3818416 and rs5351 in the ETB gene. In
Northern Han male inhabitants, T allele of rs5370 and G
allele of rs2070699 could be IS risk factors marker. While in
Northern Han women, the A allele of rs1801708 in ETA gene
is associated with IS [176]. T allele is also associated with
progression of some autoimmune diseases specifically those
accompanied with a high level of ET-1 such as primary
biliary cirrhosis (PBC) [177].
Association of Lys198Asn polymorphism with many
other sicknesses and phenotypes has been established in many
other reports. A significant association has been reported
with lower glomerular filtration rate with this polymorphism
[178]. This polymorphism, through interaction with the
endothelin ECE1 variant- ECE1B C-338A, is affecting mean
and systolic blood pressure heights in women [179]. Moreover,
reports provide a significant evidence of association
with asthma [180], and with obstructive sleep apnea (OSA)
[181].
This polymorphism is also significantly associated with
transplant-free survival of children with single-ventricle
congenital heart disease [182], and with variant angina in
Korean patients [183]. In normal tension glaucoma, TT
genotype exhibits the lowest intraocular pressure compared
with other alleles [172], Table 2.
Based on the fact that both vasodilators such as NO and
vasoconstrictors and angiogenic factors such as ET-1
regulating the retina vasculature and control the progress of
diabetic retinopathy. A case-control study of diabetic
retinopathy (DR) in type 2 diabetes in Chinese population
revealed that T allele (Asn allele) has a protective role
Ahmed and Rghigh
against DR, while nitric oxide polymorphism (Glu298Asp)
does not modulate this disease [184].
Primary nephrotic syndrome (NS) is a rare disease
occurring in childhood. Children with NS are often present
with severe edema, massive proteinuria, and hyperlipidemia
which is treated by steroids. Young et al. [185] found that
plasma ET-1 concentrations in NS pediatric patients were
significantly higher as compared to healthy children. The
ET-1 gene SNP rs10478694 (3A/4A (+138ex1ins/delA)) is
correlated with the risk of NS and correlated with plasma
ET-1 concentrations when comparing healthy children to
children with NS, while the ET-1 gene SNPs rs5370 and
rs10478694 are related to the plasma cholesterol level in
primary NS of children [185].
On the other hand, this polymorphism shows no
significant associations with many other diseases and
phenotypes such as hypertension and left ventricular mass
index in youth and left ventricular mass index in youth
[186]. In vitro, Lys198Asn polymorphism did not directly
affect the blood pressure nor the production levels of ET-1 or
big ET-1. Instead, the 3A/4A polymorphism causes plasma
ET-1 up-regulation and elevates BP.Other phenotypes, such
as ET-1 level [187], chronic obstructive pulmonary disease
(COPD) [159, 160], urinary albumin excretion [178], and
cerebral small vessel disease [188], are not linked to this
polymorphism.
This polymorphism did not contribute in myocardial
infarction risk in smoking population with confirmed
atherosclerotic lesion [189], and T-1370G polymorphism
played no role in long-term survival in patients having pump
cardiac surgery [190].
This polymorphism and other ET-1 polymorphisms such
as G8002A and T-1370G have no significant impact on
overall patient survival (OS) in locoregionally advanced
nasopharyngeal carcinoma (NPC) patients [191] and have no
role in chemoresistance in osteosarcoma (OS) in children
[192].
The paradox reports about the modulation of
hypertension by occurrence or absence of Lsy198Asn
polymorphism are attributed to the procedures and study
populations used by these studies. For instance, conclusions
from Funalot and his group [179] connecting rs5370
polymorphism to systolic and mean blood pressure came
from investigations done on the older women population
with an average age of 65 years. While Dong and other
researchers [186] made their conclusions conducting a long-
term study (15 years) and using a younger population with
an average age of 12 years.
Moreover, reports failed to link this polymorphism with
the risk of pulmonary metastatic osteosarcoma (OS), which
is the primary common malignant bone tumor in young
people (children and teenagers) [193]. Some researchers
correlate this polymorphism with the increase of ET-1 or
preproendothelin-1 level in plasma [157, 166] or with
increased responsiveness of receptors [156] although the
clear pathway by which this polymorphic ET-1 is
functioning has not been thoroughly investigated. The
increase of ET-1 synthesis and duration increases the
Polymorphism in Endothelin-1 Gene: An Overview Current Clinical Pharmacology, 2016, Vol. 11, No. 3 197

Table 2. Phenotypes and diseases altered by ET-1 Polymorphisms.

Organ or Disease or Polymorphism Type of the Study and the Effect of Polymorphism
System Phenotype

Lys198Asn T- Allele associated with greater diastolic BP in stress [136].

Among hypertensive patients, individuals carrying TT genotype are more susceptible to
coronary artery disease [158].
Lys198Asn polymorphism is linked to hypertension in overweight [164], obese [167],
and juvenile hypertension associated with obesity [169].
The presence of T increases the susceptibility to arterial hypertension [165].
Another study showed that Lys198Asn polymorphism alone does not link to blood
pressure levels, but it works by interacting with the endothelin converting enzyme-1
(ECE-1) ECE1B C-338A variant to affect the systolic and mean blood pressure levels in
women [179].
The TT carriers with poor anger control skills exhibited the greatest total peripheral
resistance index (TPRI) reactivity. People with a genetic tendency for exaggerated
vasoconstriction who also show weak little anger control skills are more susceptible to
develop stress- induced essential hypertension [173].
T allele seems to work interactively with serotonin 2A receptor polymorphism 5-HT2A
T102C to produce hypertension [163].
no sufficient data were supporting the association between K198N polymorphism and
Blood
hypertension, systolic blood pressure, lipid levels and insulin resistance or metabolic
pressure (BP)
syndrome [171].

G(8002)A, CA/CT The three polymorphisms seem to have an inner association and work in a complex
dinucleotide repeat, and manner [213]. The smoking risk factor for cardiovascular diseases such as hypertension
−3A/−4A(−138) appears to be operating through −3A allele of the −3A/−4A polymorphism [213].

Lys198Asn, 138ins/delA, Heterozygous individuals of Glu106Glu (rs5369) represent augmented BP, while those
Glu106Glu, rs1476046, carrying homozygous allele (GG) revealed lower BP. The uncommon allele (AA) was
and rs2071943. not investigated [223].

Cardiovascular T-1370G and Lys198Asp In rheumatoid arthritis individuals, Lys198Asn TT genotype is associated with
system hypertension [214].

Rs2071943. The rs2071943 polymorphism significantly linked with baseline fitness level on the
possibility of occurrence hypertension in white individuals [224].

rs1800541 and rs3087459 Strongly modulate the effect of dietary potassium on the blood pressure in Chinese
women community [215].

Rs2070699 Rs2070699 is enhancing the hypertension risk linked to rs5370 [222].

Lys198Asn T- Allele of this polymorphism accompanied with higher circulation level of ET-1 lead
to Preeclampsia [157].
Preeclampsia
T-Allele is associated with hypertension and with augmented circulation levels of ET-1
and interact with other factors to develop pre-eclampsia in gravid females [166].

Lysl98Asn Individuals carrying T- Allele displayed more susceptibility to weight gain in association
Obesity
with high blood pressure disease when compared to GG homozygotes carriers [168].

Variant Lys198Asn, +138delA, Compared to the control, Angina group, reveals higher occurrences of A8002 or Asn198
angina and G8002A polymorphisms, and lower incidence of 138delA allele [183].

Myocardial Lys198Asn This polymorphism did not contribute in myocardial infarction risk in smoking
infarction risk population with confirmed atherosclerotic lesion [189].

G(8002)A A allele is more frequent than G allele in the ischemic patients with diabetes mellitus,
who had experienced a myocardial infarction or ischemic disease of lower limbs than in
the ischemic patients without these diseases [212].
Heart Failure.
G (8002) A and -3A/-4A This polymorphism not associated with the plasma levels of ET-1 in Chronic Heart
Failure. [207].

Lysl98Asn T allele has more tendency for heart failure (HF) than G allele carriers [170]
198 Current Clinical Pharmacology, 2016, Vol. 11, No. 3 Ahmed and Rghigh

Table 2. contd….

Organ or Disease or Polymorphism Type of the Study and the Effect of Polymorphism
System Phenotype

-974 C>A, T-1370G, The "AT" haplotype (rs3087459 and rs1800541) associated with risk of developing
Glu106Glu of ET-1 ACS, while haplotypes (CT), and (AG) possibly are protective for the development
gene and rs1799983, of ACS [151].
rs2070744, rs1800783 The rs5369 polymorphism is showing no association with acute coronary syndrome
Acute coronary
of eNOS gene. (ACS) [151].
syndrome (ACS).
The A allele frequencies of the ET-1-914 T>C (rs3087459) polymorphism is
occurred more frequently in ACS patients than in controls, the "AA"
Cardiovascular genotype linked to augmented risk of developing ACS
system (twice the risk than AC heterozygous) [151].

Coronary artery G8002A A allele linked to higher endothelin-1 circulation than GG genotypes [210].
disease (CAD) and
ET-1 level.

rs1800541, rs2070699, T allele of rs5370 and G allele of rs2070699 could be IS risk factors marker [176].
Ischemic stroke (IS). and rs5370 The G allele of Rs2070699 polymorphism increases the prevalence risk to ischemic
stroke (IS) about two-fold in the Chinese Han men [176].

Lys198Asn T-Allele carrying individuals displayed more susceptibility to hearing impairment

than G allele carriers [174].
Ear Hearing diminishing T allele carriers are at higher risk of sudden sensorineural hearing loss (SSNHL)
than G allele. However, G allele carriers manifest complicated form of the disease
[175].

+138(+138/ex1ins/delA) Lys198Asn is not linked to lung diffusion tests or plethysmography in smoking

Lung diffusion and Lys198 Asn. individuals. The +138/ex1 ins/delA polymorphism probably play role in lung
Pulmonary hyperinflation [201]
metastatic (OS) T-1370G, Lys198Asp The T allele at rs1800541 linked to high incidence of pulmonary metastatic (OS).
and G2288T. While the G allele at rs2070699 has no associated with pulmonary metastatic [193].

G2288T , 3A/4A The ET-­‐1 G2288T polymorphisms showing association with High altitude
High altitude
(+138ex1ins/delA) and pulmonary oedema (HAPE) [218].
pulmonary oedema
Lys198Asn

rs5370 alone or with The T allele of rs5370 [161] or with 3A/4A genotype of +138 A; rs10478694
Pulmonary arterial
(+138 A; rs10478694) increase the individual's susceptibility to the idiopathic pulmonary arterial
hypertension (IPAH)
hypertension (IPAH) and affect its course of progression [162].

Lung and Asthma, bronchial Lys198Asn and T1370G Lys198Asn polymorphism significantly connected to Asthma [180].
Respiratory hyper-reactivity, and in the promoter region.
system. atopic asthma.

+134 3A/4A and In a study of COPD and their association to impaired exercise tolerance. 3A4A and
Chronic obstructive Lys198Asn. GG genotypes linked to higher V¢O2max values. ET-1 gene possibly modifies the
pulmonary disease cardiopulmonary system in exercise [160].
(COPD). +138 4A Allele possibly has a role in COPD pathogenesis. TT genotype of G198T
polymorphism was more common among non-COPD smokers [160].

Lys198Asn T- Allele associated with the severity of OSA in obese subjects [181].
Obstructive sleep
rs2071943 This polymorphism linked to Obstructive sleep apnea in European Americans [154].
apnea (OSA).
rs9296344 This polymorphism connected to the same disease in African Americans [154].

Rs1800997 Play a role in development and progression of pulmonary congestion as the 3A

Pulmonary
allele found to be twofold higher in the patients suffering pulmonary congestion and
congestion
severe chronic heart failure [207].

Effect on transplant- Lys198Asn T-Allele significantly linked to transplant-free survival. These results propose that
free survival for genetic variability can adapt vascular resistance [182].
Organ
children with single-
transplantation
ventricle congenital
heart disease.
Polymorphism in Endothelin-1 Gene: An Overview Current Clinical Pharmacology, 2016, Vol. 11, No. 3 199

Table 2. contd….

Organ or Polymorphism Type of the Study and the Effect of Polymorphism

Disease or Phenotype
System

Lys198Asn, T- G5665T and T-1370G linked to variations of autoantibody production while the ET A C +
Graves’ disease (GD) 1370G), ETA (C + 70G polymorphism linked to increased susceptibility to ophthalmopathy in Graves’
Thyroid 70G and G-231A) disease patients [194].
Hashimoto's thyroiditis 5665 and -1370. 5665 and - 1370, as well as EDNRA+ 70 and - 231 SNPs not associated with this disease,
(HT); although ETA + 70 polymorphism associated with decreased risk for early onset HT [217].
3A/4A, GG4A haplotype linked to the pathogenesis of IgAN [200].
Immunoglobulin A
Lys198Asn, and
nephropathy (IgAN).
T1370G
Glomerular filtration T-1370G and Haplotype G-T (compound ET-1 -1370GG/198TT genotype) associated with a lower
rate (GFR) Lys198Asp GFR and with a significantly higher susceptibility to diminished filtration [178].
Autosomal dominant K198N, 3A/4A, Polymorphisms; K198N, 3A/4A, and T-1370G have no consequences on the progression
polycystic kidney and T-1370G of autosomal dominant polycystic kidney disease (ADPKD) [209].
disease (ADPKD)
Kidney 1,536 SNPs No single nucleotide polymorphism shows correlation with Diabetic nephropathy.
(from 43 genes) Rs1476046G>A polymorphism at the endothelin-1 gene and four clustered to a 5' end
Diabetic nephropathy including NADPH oxidase homologue 4 (NOX4) haplotype were connected with Cu/Zn superoxide
rs1476046G>A. dismutase (SOD) and C- terminal pro-endothelin-1 circulating levels and might play a
role in diabetic nephropathy development [153].
rs10478694 This polymorphism linked to plasma ET-1 concentration and the risk of NS when
Primary nephrotic comparing healthy children to children with NS [185].
syndrome (NS) in
children. rs5370 and These polymorphisms connected to plasma cholesterol level in primary NS of children
rs10478694 [185].
Primary biliary Lys198Asp T allele also associated with progression of some autoimmune diseases specifically those
Liver
cirrhosis (PBC) accompanied with a high level of ET-1 such as primary biliary cirrhosis (PBC) [177].
Diabetic retinopathy Lys198Asp T allele (Asn allele) has a protective role against DR while nitric oxide polymorphism
Eye
(DR) (Glu298Asp) not modulate this disease [184].
Lys198Asp T allele of rs5370 polymorphism presented a significantly shorter median overall survival
Bevacizumab and a tendency to worse median progression-free survival. This allele could recognize
patients who unresponsive to bevacizumab [ 199].
Lys198Asp Treatment of diabetic or hyperlipidemic patients with muraglitazar (BMS-298585) found
Muraglitazar to cause less edema in individuals carrying G/G (Lys/Lys) genotype of Lys198Asn
polymorphism when compared with other groups carrying T/T (Asn/Asn) genotype [197].
Interaction Lys198Asp T allele is significantly associated with baseline diastolic blood pressure without
with drugs Nifedipine interacting with the antihypertension effects of Nifedipine (calcium channel blocker)
or treatment. [198].
-3A/-4A The -4A-4A genotype in -3A/-4A polymorphism and G allele in G8002A polymorphism
Phototherapy in
polymorphism and increase the effectiveness of phototherapy in patients with CTCL [206].
cutaneous T-cell
G allele in
lymphomas (CTCL)
G8002A.
Chemoresistant in Rs2070699 G allele of Rs2070699 associated with increased risk of chemoresistant in pediatric
pediatric osteosarcoma osteosarcoma [192].
rs2071942 and These polymorphisms related to the progress of vitiligo in the Korean population [196].
rs5370
Vitiligo T-1370G and These polymorphisms working with C+70G and G-231A polymorphisms at EDNRA gene
Skin
G5665T haplotypes have protective effects against vitiligo in Indian society. However, each single
polymorphism may not have a contributing effect in vitiligo [216].
Psoriasis 134 3A/4A 134 3A/4A has no significant association with either early- or late-onset psoriasis [205].
3A/4A and Individuals carrying the 3A/3A and 3A/4A display a significantly different ET-1 plasma
Plasma ET-1 level. Lys198Asn concentrations. The Lys198Asn polymorphism probably affects ET-1 and big ET-1 levels
ET-1 level in an indirect way [115].
Cerebrospinal fluid ET- rs2070699 This polymorphism increases ET-1 level in CSF [221].
1 level.
200 Current Clinical Pharmacology, 2016, Vol. 11, No. 3
selectivity of polymorphic ET-1 toward its receptors (ETA or
ETB) or interaction with other genes, or environmental
factors all are possible pathways. Therefore, the differences
between Lys198Asn polymorphic ET-1 and wild-type ET-1
at molecular effectiveness level and affinity toward ET
receptors are still ambiguous.
The Graves' disease (GD) manifestation observed in the
thyroid gland of GD patients such as hypervascularization,
and thyroid follicular cell hyperplasia and lymphocyte
infiltration linked with increased expression of ET-1, are
strong angiogenic and mitogenic factors [194]. Therefore,
the connection of GD to polymorphisms of ET-1 gene
[G5665T (or Lys198Asn), T-1370G] and ETA gene (C+70G
and G-231A) in a sample of a total of 165 GD patients was
investigated [194]. This study concluded no association of
this polymorphism with GD as the occurrence of this allele
has a random pattern, and no significant differences found
between patients with GD and controls [194]. However, ET-1
G5665T and T-1370G SNPs were related to altered
autoantibody production (as GD is an autoimmune disease),
and ETA C+70G SNP is related to increased risk for
ophthalmopathy in GD patients [194], Table 2.
ET-1 is known as a pro-inflammatory cytokine. It kindles
the release of a variety of other cytokines such as IL-6, IL-8
and the proliferation of T-lymphocytes, and promotes
monocyte/macrophage chemotaxis [194]. ETA mediates the
inflammatory modulator function of ET-1. Regarding the
relationship among inflammatory cells, cytokines, and
autoantibodies, it seems possible that ET-1 through ETA and
their polymorphisms can associate with autoantibody
production [194].
ET-1 is a very potent vasoconstrictor in human skin, and
its vasoconstrictor effect is primarily mediated by ETA receptors
[195]. Moreover, it has an influence on melanocytes by
regulating their homeostasis, and controlling proliferation
and pigmentation. Some researchers thought that it may
contribute in the skin response to ultraviolet irradiation and
plays a role in the development of vitiligo [196]. ET-1
polymorphisms; rs2071942 and rs5370 are related to the
progress of vitiligo in the Korean population [196].
EFFECT ON DRUGS
Muraglitazar is peroxisome proliferator-activated
receptor gamma (PPARgamma) agonist- that belongs to
thiazolidinedione class of compounds (TZD)
antihyperglycemic drug at clinical trial, this drug has a great
incidence of edema and heart failure in susceptible individuals.
Treatment of diabetic or hyperlipidemic patients with
muraglitazar (BMS-298585) was found to cause less edema
in individuals carrying G/G (Lys/Lys) genotype of Lys198Asn
polymorphism when compared with other groups carrying
T/T (Asn/Asn) genotype [197].
In another study, T allele was found to be significantly
associated with baseline diastolic blood pressure without
interacting with the antihypertension effects of Nifedipine
(calcium channel blocker) [198].
Bevacizumab is a medication used in metastatic breast
cancer. The inconsistency of drug effects among patients
Ahmed and Rghigh
seems modulated by polymorphisms of genes involved in
angiogenesis and hypertension such as ET-1, vascular
endothelial growth factor-A (VEGF-A), VEGF receptor 1
(VEGFR-1), serine threonine kinase 39 (STK39). T allele of
rs5370 polymorphism presented a significantly shorter
median overall survival and a tendency to worsen median
progression-free survival. This allele could recognize
patients who are unresponsive to bevacizumab [199].
Rs1800997; 3A/4A (+138ex1ins/delA) Polymorphism
3A/4A (+138ex1ins/delA) polymorphism; rs1800997
(Formerly rs10478694) is insertion/delete polymorphism
located at exon-1, position; Chr6:12398714 with genotypes
of wild type; 3A3A, heterozygous; 3A4A, and homozygous;
4A4A.
Patients with immunoglobulin nephropathy (IgAN) can
develop end-stage renal failure (ESRF) over years. In this
disease, the immunoglobulin A or its immune complexes
(IgA-ICs) causes diffused mesangial deposition which leads
to a mesangial proliferative glomerulonephritis disease.
Three polymorphisms namely Lys198Asn, 3A/4A and T-
1370G were investigated for their relation to the
development and progression of the IgAN in the Czech
population. In a single-gene analysis, no effect of these
polymorphisms was found, although the ET-1 haplotype of
GG4A (G-198, G-1370 and 4A alleles) was found to be
significantly linked with the occurrence of immunoglobulin
nephropathy in patients [200].
In another study, the presence of the +138 insertion A
polymorphism was thought to be implicated in chronic
obstructive pulmonary disease COPD pathogenesis [159,
160]. Moreover, this polymorphism is associated with lung
hyperinflation in smoking people [201], and idiopathic
pulmonary arterial hypertension (IPAH) [202].
ET-1 is a polypeptide involved in inflammation [203]
and acts as pro-inflammatory in airways thus contributing in
many diseases such as chronic obstructive pulmonary disease
(COPD). The relation between ET-1 and other several
inflammatory markers such as C-reactive protein (CRP),
erythrocyte sedimentation rate (ESR), levels of testosterone,
free testosterone, follicle stimulating hormone (FSH) and
luteinizing hormone (LH) has become an interesting area to
explore. The 3A/4A genotype is associated with lower levels
of testosterone and free testosterone in COPD male
- individuals, and prone to increase the intensity of systemic
inflammation [203]. This genotype also inverses the
correlation between testosterone and CRP [203].
ET-1 has a role in skin constriction and inflammation
[204] and probably acts interactively with bradykinin [205],
some reports investigate the possible role of ET-1 gene
polymorphisms in psoriasis. The 134 3A/4A gene poly-
morphism has no significant association with either early- or
late-onset psoriasis [205].
ET-1 also affects the angiogenetic and antioxidant
properties of blood vessels and contributes in the cutaneous
T-cell lymphomas (CTCL) diseases responsiveness to
phototherapy [206]. The -4A-4A genotype in -3A/-4A
polymorphism and G allele in G8002A polymorphism
Polymorphism in Endothelin-1 Gene: An Overview
increases the effectiveness of phototherapy in patients with
CTCL [206].
The circulation levels of big ET-1 and ET-1 in plasma
can be used as a sensitive tool for diagnosis of some
cardiovascular diseases such as chronic heart failure. Many
polymorphisms affect the level of these polypeptides in
plasma, in one study a significant difference in ET-1
concentrations reported among individuals carrying 3A/3A
and these carrying 3A/4A genotypes, the 3A/4A genotype
was associated with higher concentration of ET-1 [187].
Other polymorphisms such as G (8002) A were suspected to
have the same effect; studies detected no association
between plasma levels of ET-1 or big ET-1 and these
polymorphisms [207]. Based on the forementioned fact that
3A/4A polymorphism genotype increases ET-1 levels in
plasma which theoretically could increase the blood
pressure, a study assumed association of 3A/4A genotype
with BP elevation through plasma ET-1 up-regulation [187].
However, other studies failed to detect any significance
associated with either hypertension or orthostatic
hypotension risk in a Chinese population [208].
Rs1800997 polymorphism seems to play a role in
development and progression of pulmonary congestion as
the 3A allele was found to be two-fold higher in the patients
suffering pulmonary congestion and severe chronic heart
failure. This type of association was possibly facilitated by
the tissue endothelin system [207], Table 2.
Polymorphisms; K198N, 3A/4A, and T-1370G have no
consequences on the progression of autosomal dominant
polycystic kidney disease (ADPKD) [209].
Rs2071942; G8002A Polymorphism
G8002A (rs2071942) polymorphism is occurring in
intron 4 and has genotypes as follows: wild type; GG,
heterozygote; AG, and homozygote; and AA.
Conflicting reports are present in the literature
concerning the relation of this polymorphism with the ET-1
concentration. The A alleles (either AA or AG) in patients
suffering from coronary artery disease (CAD) in Turkish
population are significantly connected to the high level of
circulating ET-1 in plasma [210]. While in acute coronary
syndromes (ACS) in Tunisian patients, the AA genotype is
related to lower concentrations of ET-1, the AG is linked to
intermediaries’ values, and the GG is associated with higher
levels of ET-1 [211]. In the controversy with these reports, a
previous study [207] showed no associations of this
polymorphism with the levels of the circulating endothelins
(ET-1 ana big ET-1).
Some reports provide evidence connecting this
polymorphism to ischemic disease of lower limbs and
occurrence of myocardial infarction in diabetes mellitus
population with heart failure. An allele is more frequent than
G allele in the ischemic patients with diabetes mellitus, who
had experienced a myocardial infarction or ischemic disease
of lower limbs than in the ischemic patients without these
conditions [212]. Also, the polymorphisms of A8002 or
Asn198 were found to be more common in variant angina
patients than in normal Korean patients [183].
Current Clinical Pharmacology, 2016, Vol. 11, No. 3 201
The G allele in G8002A polymorphism increases the
effectiveness of phototherapy in patients with cutaneous T-
cell lymphomas (CTCL) [206]. However, it has no effect on
overall patient survival (OS) in locoregionally advanced
nasopharyngeal carcinoma (NPC) patients [191].
Reports indicate the presence of significant inner
relations inside the ET-1 gene between three ET-1 gene
polymorphisms namely CA/CT dinucleotide repeat,
G(8002)A and −3A/−4A (alleles G with −3A and A with
−4A). These polymorphisms are working in a complicated
manner to interact with cardiovascular risk factors such as
hypertension but showed no evidence of explicit interaction
with cardiovascular risk factors such as body mass index.
The incidence of −3A allele of the −3A/−4A polymorphism
was significantly detected in the smokers group when
compared to nonsmokers [213]. The smoking risk factor for
cardiovascular diseases such as hypertension seems to be
operating through this ET-1 gene variant [213], Table 2.
Rs1800541; T-1370G Polymorphism
This polymorphism (rs1800541) was found in the
promoter region of ET-1 gene, at position Chr6:12397204,
with genotypes of wild type; GG, heterozygote; TG, and
homozygote; TT.
The glomerular filtration rate (GFR) is lower in G- T
haplotype carriers (compound ET-1 -1370GG/ 198TT
genotype as noticed by using haplotype analysis) when
compared with remaining subjects [178].
Rheumatoid arthritis patients carrying haplotype of the
rs1800541-rs5370 T-T ET-1 have more tendency of
developing hypertension disease with high systolic blood
pressure, and pulse pressure [214]. The ET-1 system
regulates blood flow, water, sodium reabsorption, and acid-
base balance. At a small concentration in the picomolar
range, ET-1 can contract the renal vasculature through ETA
receptors; thus, can control the influence of several
electrolytes on BP [63]. Polymorphisms rs1800541 and
rs3087459 powerfully modulate the effect of dietary
potassium on the blood pressure in Chinese women
community [215].
The T allele of rs1800541 polymorphism was found to be
connected with high susceptibility to pulmonary metastatic
osteosarcoma (OS) in a study performed on a large
population of patients and healthy controls [193]. No
significant association was observed for the rs1800541
polymorphism with hypertension or with circulation levels
of ET-1 in both patients and healthy controls. This may
suggest that hypertension or plasma levels of ET-1 play no
role in OS metastases. Rs1800541 polymorphism was
functionally found to be working through alteration of the
mRNA and the secreted protein levels of ET-1 in OS cell.
The TT homozygotes conveyed a significantly greater
relapse rate when is compared to GG homozygotes which are
showing a significantly higher complete recovery rate than
other genotypes (TG or TT) [193], Table 2.
The G allele at rs1800541 is associated with reduced risk
of chemoresistant Pediatric Osteosarcoma (OS). The
rs1800541-rs2070699 haplotypes TG are associated with
202 Current Clinical Pharmacology, 2016, Vol. 11, No. 3
increased risk of chemoresistant in (OS), while the GT
associated with increased risk of chemoresistant in pediatric
OS [192]. In other cancers, such as nasopharyngeal
carcinoma (NPC), T-1370G genotypes have no significant
effect on patient overall survival (OS) [191].
The polymorphism rs1800541 is represented in some
references as ET-1-1394 T>G (Instead of T-1370G), and the
interaction of this polymorphism with ET-1-974 C>A
polymorphism (rs3087459) showed a strong linkage with
acute coronary syndrome (ACS). The H1 "AT" haplotype
was associated with risk of developing ACS, while
haplotypes (CT), and (AG) possibly are protective for the
development of ACS [151], Table 2.
There was no notable association of this polymorphism
with Graves' disease (GD). However, ET-1 G5665T and T-
1370G SNPs were related to altered autoantibody production
in this disease [194], Table 2. This polymorphism has no role
in the long-term survival of patients having pump cardiac
surgery [190], and did not contribute in ischemic stroke (IS)
in the Chinese Han population in northern China [176], and
did not affect the progression of autosomal dominant
polycystic kidney disease (ADPKD) [209]. Moreover, the T-
1370G and G5665T polymorphisms at ET-1 gene and
C+70G and G-231A polymorphisms at ETA gene haplotypes
have protective effects against vitiligo in Indian population.
However, each single polymorphism may not have a
contributing effect on vitiligo [216]. Same polymorphisms
were studied in relation with Hashimoto's thyroiditis (HT);
5665 and - 1370, as well as ETA+ 70 and - 231 SNPs were
not associated with this disease although ETA + 70
polymorphism was found to be associated with decreased
risk for early onset HT [217].
Rs2070699; G2288T Polymorphism
G2288T Polymorphism (rs2070699) occurs in the intron-
2 region of ET-1, position; Chr6:12400757, with genotypes
of wild type; GG, heterozygote; TG, homozygote; TT.
Rs2070699 polymorphism is linked to high altitude
pulmonary edema (HAPE), which is altitude illness that
occurs in a severe form in travelers on the rapid climb to
heights more than 2500 meters. This disease manifests as
pulmonary hypertension, uneven vasoconstriction, and over
perfusion causing stress failure of pulmonary capillaries
leading to alveolar flooding [218].
ET-1 exists in high levels in cerebrospinal fluid (CSF)
after subarachnoid hemorrhage (SAH) associated with
increased risk of cerebral vasospasm [219] and may play a
role in delayed cerebral ischemia (DCI) [220]. The ET-1
protein levels in cerebrospinal fluid (CSF) were investigated
in small groups of subjects at high risk of cerebral
vasospasm [221]. rs2070699 polymorphism was thought to
play a role in the high level of ET-1 in CSF [221].
The G allele of Rs2070699 polymorphism increased the
prevalence risk to ischemic stroke (IS) about two-fold in the
Chinese Han men [176], enhanced the hypertension risk
linked to rs5370 [222], Table 2, and was found to be
associated with increased risk of chemoresistant in pediatric
osteosarcoma [192]. However, it has no significant
Ahmed and Rghigh
connection with the susceptibility to pulmonary metastatic
[193], Table 2.
Rs 5369 (Glu106Glu) Polymorphism
Glu106Glu (Rs5369) is a synonymous DNA change in
exon 3, position; Chr6:12402243, with genotypes of wild
type; GG, heterozygote; AG, homozygote; AA.
In one study, this polymorphism was reported to be
linked to blood pressure (BP) when investigated with the
consideration of job strain influence. With high job strain,
the individuals carrying AG genotype displayed higher blood
pressure than the individuals carrying GG when compared to
corresponding groups of same genotype carriers at low job
strain [223]. The sample size is one of the drawbacks of this
study. Moreover, the association between the blood pressure
and job stress in homozygous genotype (AA) for rs5369
polymorphism was not investigated [223].
Based on the background of atherosclerotic lesions are
fundamentally affected by the endothelial dysfunction. The
fact that endothelial nitric oxide synthase (eNOS) and ET-1
are considered important molecules in the endothelial
dysfunction process; several eNOS and ET-1 gene
polymorphisms were evaluated as susceptibility markers for
acute coronary syndrome (ACS). This study suggested that
Rs5369 polymorphisms have no contribution in acute
coronary syndrome (ACS) [151], Table 2.
Rs3087459; -974 C>A Polymorphism
Rs3087459 is a single nucleotide variation at the
promoter region, position; Chr6:12397624, with genotypes
as follows: wild type; CC, heterozygote; AC, and homozygote;
AA.
Experimental studies have shown that ET-1 and
endothelial eNOS play a significant role in the development
of the atherosclerotic plaque [151]. Therefore, six poly-
morphisms, three (Asp298Glu, −786 T>C, and −1474 A>T)
located in the eNOS gene and three (−974 C>A, −1394 T>G,
and Glu105Glu) located in the ET-1 gene were investigated.
In humans, these polymorphisms were linked to the low and
irregular expression of eNOS and ET-1. In a group of 452
Mexican individuals suffering from acute coronary
syndrome (ACS) and 283 healthy controls, increased
frequencies of the A allele of the ET-1-914 T>C (rs3087459)
polymorphism in ACS patients was observed as compared to
controls. Under an additive model, the "AA" genotype was
found to be linked with the augmented risk of developing
ACS (twice the risk than AC heterozygous), adjusted for
gender, hypertension, dyslipidemia, alcohol consumption,
smoking, and diabetes.
The EDN1-1394 T>G and EDN1-974 C>A polymorphisms
showed a strong linkage disequilibrium (D′′ = 0.86) and were
used to construct four haplotypes, H1 (AT), H2 (CG), H3
(CT), and H4 (AG). Patients with ACS displayed increased
frequency of H1 and decreased frequencies of H3 and H4
haplotypes when compared to healthy control individuals.
The H1 "AT" haplotype was reported to be associated with
risk of developing ACS after adjusting for cardiovascular
risk factors using multiple logistic analyses and possible two
Polymorphism in Endothelin-1 Gene: An Overview
protective haplotypes H3 (CT), and H4 (AG) for the
development of ACS [151], Table 2.
This polymorphism participated in the influence of
dietary potassium on the blood pressure in the rural Chinese
population [215]. The rs3087459A>C and rs1476046G>A
polymorphisms seemed to display augmented risk to diabetic
nephropathy [153].
Rs1476046 Polymorphism
Rs1476046G>A is a single nucleotide variation at the
intron-2 region, position: chr6:12401206-12401207 with
genotypes as follows: wild type; GG, heterozygote; GA, and
homozygote; AA.
The main long-term vascular complication of type II
diabetes is diabetic nephropathy. To explore the association
of many polymorphisms and possible intermediate phenotype
such as corresponding circulating protein levels related to
these polymorphisms with this disease some polymorphisms,
and their related phenotypes were selected and studied (i.e.
common and rare). The diabetic individuals were divided
into two subgroups in a case–control study; with and without
diabetic nephropathy. These polymorphisms were selected
among 43 associated genes in diabetic nephropathy
population by a modified microarray of 1,536 SNPs among
1,048 Chinese patients population. Any links at the best
∼1% between diabetic nephropathy and any polymorphism
were examined and described in this study. Several intronic
SNPs were considered for this study including variants from
four gene regions namely NADPH oxidase homologue-4
(NOX4), ET-1, nitric oxide synthase-1 (NOS1), NADPH
oxidase homologue-1 (NOX1) in addition to coding non-
synonymous rs2071756C>T (Arg315His) from NOX1 (X
chromosome) [153].
In this study, the heterozygous (GA) and homozygous
minor allele (AA) in ET-1 gene polymorphism
rs1476046G>A showed higher circulating C-terminal pro-
endothelin-1 levels among diabetic nephropathy individuals
compared to control individuals, suggesting a contribution of
endothelin-1 in the progression of this disease. Interestingly,
the rs1476046G>A minor allele (AA) was associated with
low circulating levels C- terminal pro-endothelin-1 in control
individuals. Linear regression analysis reveals a reduction in
circulating C- terminal proendothelin-1 level by 3.60±1.35
pmol/L with the presence of each copy of the allele (A). This
relationship does not occur among cases. Moreover,
endothelin-1 5′ haplotype AA (frequency: 0.129, formed by
rs3087459A>C and rs1476046G>A) seemed to cause
augmented vulnerability to diabetic nephropathy [153],
Table 2.
This polymorphism is suspected to have a role in the
effect of dietary potassium on blood pressure in the rural
Chinese population [215].
Rs2071943 Polymorphism
Rs2071943 polymorphism at position: chr6:12295814 in
ET-1 gene is a single nucleotide variation that occurs at
intron 4 with genotypes as follows: wild type; GG,
heterozygote; GA, homozygote; AA.
Current Clinical Pharmacology, 2016, Vol. 11, No. 3 203
It is hypothesized that the genes inside the pathways
involved with obesity, craniofacial development,
inflammation, and ventilatory regulation have a great impact
on the obstructive sleep apnea (OSA). ET-1 is a potent
vasoconstrictor involved in hypertension disease. In ET-1
knockout mice, endothelin-1 is connected with respiratory
failure at birth, and also associated with hypoventilation.
Mice with one functional ET-1 gene show inadequate
ventilatory response when stimulated with hypoxemia or
hypercapnia. Moreover, ET-1 gene knockout mice showed
noticeable craniofacial morphologic anomalies manifested as
irregular pharyngeal arch development similar to that in
humans with OSA triggered by Treacher Collins syndrome
and Pierre Robin syndrome. Apnea-hypopnea index (AHI)
increment was noticed among European population carrying
T allele of rs5370 polymorphism [154]. This allele also
revealed an augmented susceptibility to Apnea-hypopnea
index superior to or equivalent to 15 in the population of
European Americans. Obstructive sleep apnea (OSA) which
is the most common type of sleep apnea and is caused by
obstruction of the upper airway was found to be linked to
rs9296344 polymorphism in ET-1 gene in a population of
African Americans, while the rs2071943 polymorphism in
ET-1 gene was reported to be associated with the same
disease in European American individuals. The later
polymorphism; rs2071943 was in linkage disequilibrium
with rs5370 [154], Table 2.
The development and progression of coronary artery
disease among young black, and white population was
assessed in a sample of 2663 contributors. The risk factors
such as baseline fitness and baseline body mass index with
the occurrence of hypertension over 20 years were studied
and explored for any link with single nucleotide
polymorphisms selected from different seven genes.
The individuals that developed hypertension disease from
both races; blacks and whites reveal significantly higher
blood pressure and BMI, and inferior fitness (blacks only)
when compared to the normotensive contributors that
showed less BMI, lower hypertension, and good fitness.
Some polymorphisms in genes, such as peroxisome
proliferative activated receptor gamma co- activator 1α
(PPARGC1A) and bradykinin β2 receptor (BDKRB2) genes,
were found to be linked with high vulnerability to high blood
pressure disease. Other polymorphisms were connected to
less vulnerability to high blood pressure disease such as one
polymorphism at the BDKRB2 gene and another one at
endothelial nitric oxide synthase- 3 (NOS3) genes. The
relationship between baseline fitness and the susceptibility to
hypertension disease was explored under the effect of some
controlling polymorphisms located at angiotensin converting
enzyme, angiotensinogen, BDKRB2 and NOS3 genes in
black individuals and with the BDKRB2, ET-1 (rs2071943)
and PPARGC1A genes in white contributors.
In both races, the rs4900318 polymorphism located at
BDKRB2 gene displayed insignificant interactions with
baseline fitness on the vulnerability to high blood pressure
disease. The influence of BMI was on the vulnerability to
high blood pressure disease altered by G- protein β3-subunit
(GNB3) rs2301339 genotype in white individuals. In
204 Current Clinical Pharmacology, 2016, Vol. 11, No. 3 Ahmed and Rghigh

conclusion, as all of these associations were statistically
insignificant, the studied polymorphisms in these selected
genes have no effect on the way of the association between
baseline fitness and BMI with the vulnerability to high blood
pressure disease [224].
In another study, the rs2071943 polymorphism was
found to have no clear role in ambulatory blood pressure
when it was investigated in relation to job strain [223], Table
2.
Rs9296345 Polymorphism
Rs9296345 polymorphism, located at position:
chr6:12298333 in ET-1 gene, is a single nucleotide variation
with genotypes as follows: wild type; CC, heterozygote; CT,
and homozygote; TT.
ET-1 plays a critical role as regulator of blood pressure.
Therefore, the association of ET-1 gene with the
vulnerability to high blood pressure disease in relation to
induced changes in blood pressure as a result of endurance
training was examined in exercise training and genetics
family study cohorts.
Rs9296345 polymorphism has no influence on the blood
pressure when studied in association with rs5370
polymorphism in white participants including incident
hypertensive case patients compared to normotensive control
individuals [155].
smokers, and obstructive sleep apnea. In eyes, T allele has
lowest intraocular pressure in glaucoma and plays a
protective role against diabetic retinopathy. This allele
modulates autoantibody production Graves' disease, and is
related to the progress of vitiligo, increases unresponsive to
bevacizumab, and causes oedema in patients treated with
muraglitazar.
Some significant associations with many other different
phenotypes especially those related to cardiovascular system
diseases such as hypertension, chronic heart failure, ischemic
diseases, angina, oedema, and coronary disease have been
reported. Some of these polymorphisms were studied in
relation to each other, thus; some inner complex association
was also described. In the future, the genotyping of ET-1
could be considered as a diagnostic marker and a tool for
determining the treatment approach.
ABBREVIATIONS
ET-1 also EDN1 = Endothelin-1
ET-2 also EDN2 = Endothelin-2
ET-3 also EDN3 = Endothelin-3
VIC = Endothelin β or mouse vasoactive
intestinal contractor
ETA = Endothelin (ET) receptor subtypes
A

SUMMARY ETB = Endothelin (ET) receptor subtypes B

The present review suggests that endothelin-1 genetic EDAF = Endothelium derived relaxing factor
polymorphism could have a significant role in determining B-ET = Big-endothelin
several ET-1 related disorders particularly cardiovascular
diseases and also could have an inordinate impact on some ECE = Endothelin converting enzyme
drug effect. Many endothelin-1 gene polymorphisms, such as SNPs = Single nucleotide polymorphisms
Lys198Asn (rs5370), 3A/4A (+138ex1ins/delA) (rs1800997),
G (8002) A (rs2071942) and T1370G (rs1800541), COPD = Chronic obstructive pulmonary
increase the ET-1 level in circulation and some increase disease
the receptors responsiveness to the ET-1. On the other
OSA = Obstructive sleep apnea
hand, polymorphism rs1476046 decreases preproET-1’
preproendothelin-1 in the circulation. OS = Osteosarcoma
Lys198Asn (rs5370), (Glu106Glu) (rs5369), T1370G GD = Graves' disease
(rs1800541) and Rs2071943 polymorphisms increase the
TZD = Thiazolidinedione
blood pressure, while other polymorphisms such as
rs9296345 have no effect on blood pressure. IgAN = Immunoglobulin A nephropathy
Lys198Asn (rs5370) is the most extensively studied CAD = Coronary artery disease
polymorphism in the literature. T allele is related to higher
ET-1 levels, increased receptor responsiveness to ET-1, GFR = Glomerular filtration rate
increased the risk to develop coronary artery disease and PP = Systolic blood pressure (SBP), and
heart failure, ischemic stroke, variant angina, and induced pulse pressure
hypertension. Moreover, T allele caused obesity, hearing
impairment, sensorineural hearing loss, primary biliary ACS = Acute coronary syndrome
cirrhosis, and in Kidney, this allele is related to lower HAPE = High altitude pulmonary edema
glomerular filtration rate, and also related to the plasma
cholesterol level in the primary nephrotic syndrome in NOX4 = NADPH oxidase homologue-4
children. NOS1 = Endothelin-1, nitric oxide synthase-1
T allele is linked to asthma, increases individual's NOX1 = NADPH oxidase homologue-1
susceptibility to the idiopathic pulmonary arterial
hypertension, chronic obstructive pulmonary disease in non- OSA = Obstructive sleep apnea
Polymorphism in Endothelin-1 Gene: An Overview
BMI = Body mass index
PPARGC1A = Proliferative activated receptor
gamma co-activator 1α
BDKRB2 = Bradykinin β2 receptor
NOS3 = Endothelial nitric oxide synthase-3
CARDIA = Coronary Artery Risk Development
in Young Adults Study
GNB3 = G-protein β3-subunit
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
Declared none.
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