AN INVESTIGATION OF THE RELATIONSHIP BETWEEN THE
eNOS GENE POLYMORPHISM AND DIAGNOSED MIGRAINE
Güler S1,*, Gürkan H2, Tozkir H2, Turan N3, Çelik Y1
*Corresponding Author: Sibel Güler, M.D., Department of Neurology, Trakya University Faculty of Medicine,
Balkan Yerleşkesi, 22030 Edirne, Turkey. Tel: +90-284-236-49-81. Fax: +90-284-223-42-03. E-mail: drsibleguler@
yahoo.com
page: 49
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DISCUSSION
Migraine is a neurovascular disorder that particularly
affects females and may cause significant
disability [7]. The pathogenesis of migraine is fairly
complex, and is not yet clear. Several previous
studies have investigated candidate genes affecting
endothelial function, such as eNOS, inducible NO
and vascular endothelial growth factor (VEGF),
and studies investigating gene-gene interaction are
more effective in increasing our understanding of the
genetic basis of migraine [8]. Genetic patterns can
change in terms of ethnic and racial properties. Thus,
the results of gene polymorphism studies conducted
in different countries and in people with different
ethnicity and race can differ from one another. Our
study examined patients and healthy controls living
in the city of Edirne in the Thrace region of Turkey.
There are few immigrants in this region, and no massive
population exchange has occurred, meaning that
demographic properties have been preserved. In the
present study, we proposed an association between
eNOS polymorphisms and frequency, severity and
duration of headaches.
In previous studies, it has been shown that
healthy individuals suffering from migraine-like
headaches, when they use medications containing
NO [9]. Moreover, administration of NO inhibitors
due to their anti-migraine effects, is consistent with
the concept of abnormal NO formation contributing
to the pathogenesis of migraine [10]. In this respect,
while NO formation is mostly attributed to the activity
of three different NOS [endothelial (eNOS),
neuronal (nNOS) and inducible NOS (iNOS)], it is
possible that the excessive amounts of NO, possibly
contributing to migraine, are derived from increased expression and activity of iNOS [11,12]. Although
iNOS is primarily regulated at the transcriptional
level, the association of the promoter region of the
iNOS gene with migraine susceptibility was also examined
[13,14].
Haplotype analysis is important, because the
analysis of genetic combinations in the involved region
and effects of genetic markers can provide further
information, if they are examined properly [13].
Mansur et al. [12] studied the functional and clinical
association of iNOS genetic polymorphism [the C–
1026A polymorphism (rs2779249) in the promoter region,
and the G2087A polymorphism (rs2297518) in
exon 16] with migraine with or without aura, and also
the association of iNOS haplotypes with migraine
[12]. While the H4 haplotype is associated with migraine
with aura (that combines both A alleles), the
presence of the A allele and H4 haplotype for the
G2087A polymorphism has been shown to increase
the tendency. Considered together, these findings reveal
that the A allele for the G2087A polymorphism is
a predisposing factor for aura development in patients
with migraine. It has been shown that the tendency
to develop migraine with aura increases when the A
allele is combined with the C–1026A polymorphism
[12]. Thus, the association between iNOS activity
and development of migraine was detected. It has
also been reported that patients, who are at-risk of developing
migraine with aura, may be detected earlier
and can benefit from selective or non selective iNOS
inhibitors [12]. Therefore, the individuals who have
genetic expression and increased iNOS activity associated
with genetic markers, are expected to benefit
more from treatment with selective iNOS inhibitors.
In some migraine cases, in addition to nausea,
vomiting, photophobia and phonophobia, temporary
neurological symptoms that occur before the onset of
headaches, and known as aura, have been observed
[15]. Migraine with aura is especially associated
with cerebrovascular and cardiovascular disease risk.
There is much evidence to suggest that NO is active
in the pathophysiology of migraine and aura, and it
exerts its effects via control of cerebral blood flow,
nociceptor activation in the trigemino-vascular system
and vasoactive neuropeptide release during neurogenic
inflammation response. It has been reported
that genes responsible for regulation of endothelial
function are important in people who are susceptible
to migraine. Therefore, it has been claimed that eNOS
gene polymorphisms create a genetic predisposition
to migraine.
Migraine and cerebrovascular disease, especially
association with ischemic stroke, is one of the most
confusing neurological problems. Although the two
disorders have differing epidemiologies, case-control
and population-based studies have shown that there is
a significant association between ischemic stroke and
migraine. Indeed, migraine with aura in particular, is
an independent risk factor for ischemic stroke [16].
Previous studies have shown that gliceryl trinitrate
can cause migraine-like headaches by turning into
NO, and L-MMA (L-nitromonomethylarginine), a
potent anti-migraine and NOS inhibitor, is effective
in those cases [17]. However, the mechanism by
which NO triggers migraine has not been identified.
In particular, an increased risk of ischemic stroke and
cardiovascular diseases should be the focus in female
patients with migraine-related endothelial dysfunction
and migraine with aura [18]. In our study, we
detected no statistically significant association between
eNOS rs743506, rs207468799, rs2070744,
rs1799983, rs148554851, rs180079 and rs3918226
gene polymorphisms and ischemic stroke, cardiovascular
and cerebral medical history.
The correlation between vasodilation, headache
and, thereby, NO presence, has been shown in previous
studies. Thus, the important role of detected
genetic variations in eNOS in the pathogenesis of migraine
with aura has been reported [19]. In contrast,
we did not detect a similar correlation for migraine
with aura. It has been indicated that differences in ethnic
groups plays a main role in distribution of eNOS
variants [20]. Knowledge of the differences in haplotype
frequency and association between variants
is thought to provide a better understanding of the
role of eNOS in cardiovascular and cerebral diseases.
We determined significant differences in the
distributions of eNOS haplotypes in patients with
migraine, with and without aura. The GA genotype
of the tag single nt polymorphism (tagSNP) rs743506
showed protective effects and the haplotypes “C C a
Glu G” and “C C b Glu G” were associated with aura
in migraine patients. This shows that eNOS genetic
variations can increase aura progression. However,
the decision-making mechanism is not certain. Furthermore,
it has been claimed that different isoforms,
known as nNOS, and their polymorphisms, may be
capable of playing a role in migraine progression [5].
Haplotype analysis, combinations of genetic
markers within a chromosome cluster location, is
valuable because it provides a more powerful approach
to genetic studies. Because only the analysis
of a single nt can be performed each time, it is possible
to eliminate inconsistencies [21]. While the association
between individual eNOS polymorphisms
and concentration changes of nitrate in blood cannot
be detected, Metzger et al. [22] have shown that
the specific and unifying eNOS gene alleles of the
selected eNOS haplotype, is associated with low nitrate
concentrations in blood of apparently healthy
individuals. The haplotype-specific expression pattern
has also been shown for eNOS, that was determined
by variants of the eNOS gene [23]. Intensive
effort has been made to verify the clinical markers of
NO formation [24,25]. Nitric oxide-induced soluble
guanylyl cyclase is one of the most important biological
effects produced by NO, thereby, the concentration
of cyclic guanosine 3,5 monophosphate
(cGMP) increases. Previous studies reported that an
eNOS poly-morphism alone has no important effect
on NO formation, however, combined with specific
haplotypes, it has been reported to have important
effect. Thus, it significantly does not affect in vivo
bioavailability of NO. In our study, we demonstrated
that the AGGTGGA haplotype constitutes a risk in
patients with migraine in terms of severity and duration,
and also that risk is higher in patients with
migraine with aura. Consistent with the literature,
specific haplotypes have higher and more specific
effect on NO formation, and this constitutes one of
the most important results of our study.
Plasma concentrations of cGMP have been reported
to have no significant effect on eNOS polymorphisms
and its haplotypes [26]. Considering
the specific eNOS genotypes alone, it is uncertain
whether or not eNOS haplotypes have an important
contribution to the formation of NO. In the literature,
it has been reported to have an important relationship
in terms of NO formation between C-4b-Glu hap-lotype
of eNOS and low nitrite/nitrate concentrations in
blood [22]. In another study, the C-4b-Glu haplotype
has been shown to be common in Black individuals
with lower nitrite concentrations in plasma and
whole blood compared to individuals with higher
nitrite concentrations in plasma. These findings were
similar to the results of studies in Caucasian individuals.
Rather than ethnic classification, this condition
shows that the genetic markers have a more important
role in NO formation [27]. Another study that shows
no association in healthy individuals between C-4b-
Glu haplotype and development of cardiovascular
disease, suggests studying C-4b-Glu haplotypes in
individuals with cardiovascular disease.
In the literature, the effects of eNOS tagSNPs
rs3918188, rs743506 and rs7830 haplotypes to NO
bio-availability in Black individuals have been studied
[28]. The frequency of the CA genotype for tag-
SNP rs7830 haplotype and C-G-A haplotype has been
found to be higher in individuals with lower blood
nitrate concentration compared to individuals with
higher blood nitrate concentration, although there
was no significant difference in genotype results according
to several investigations after multivariate
analyses [28]. The effects of rs7830 tagSNP on blood
nitrate concentrations have been shown and it was
considered that a tagSNP may be a marker to indicate
risk factors for cardiovascular disease.
Our study is the first to have investigated an association
between seven eNOS gene polymorphisms
and migraine. In previous studies of eNOS polymorphisms
in the Edirne region, no associations have
been detected between migraine and eNOS variable
number of tandem repeats (VNTR) (eNOS 4a/b)
[29], and between stroke patients and a Glu298Asp
eNOS polymorphism [30]. In our study, the lack of
a significant association between genotype and allele
frequency of the eNOS rs743506, rs207468799,
rs2070744, rs1799983, rs148554851, rs180079 and
rs3918226 gene polymorphisms in migraine patients
and the control group may arise from ethnic differences
in the populations.
Although migraine pathogenesis is not exactly
understood, genetic and environmental factors are
known to have an effect. We hypothesize that our
results provide significant data regarding the Edirne
geographical region. When our study is evaluated
alongside other studies that have been carried out
with different populations and ethnic groups, it allows
us to better understand the role of eNOS polymorphisms
in migraine pathogenesis. Determination
of genetic factors in migraine etiopathogenesis can
inform important changes in treatment strategies.
Therefore, it has been claimed that the loss of productivity
in the workplace and the social disability
resulting from migraine, which negatively affects
quality of life, can be considerably reduced.
In conclusion, this study demonstrated that there
was no significant association between the eNOS
rs743506, rs207468799, rs2070744, rs1799983,
rs148554851, rs180079 and rs3918226 gene polymorphisms
and migraine with or without aura,
whether complicated or not, in the Turkish individuals
we examined. Our results showed that the eNOS
rs1799983, rs743506, rs2070744 and rs180079 gene
polymorphisms can be a risk factor in migraine duration
and severity in particular. Moreover, in our
study, according to haplotype analysis results, the
AGGTGGA haplotype has been shown to increase
the severity and the duration of migraine more significantly
in patients with migraine with aura, compared
to patients with migraine without aura. The AGGTGGA
haplotype increases migraine-related disability
and deterioration in quality of life, and it constitutes
one of the most important results in our study. This
condition may be associated with low blood nitrate
concentrations. As with cardiovascular disease, abnormalities
of NO formation may be a risk factor for the
development of debilitating migraine with aura. But,
these data should be built on, via studies in different
populations and that use a higher number of patients.
The relationship between migraine and the
NOTCH4 gene, mapped on chromosome 6p21.3,
has been intensively investigated [31,32]. While no
significant association between R1346P and G835V
NOTCH4 gene poly-morphisms and patients with
migraine with or without aura and control groups
has been detected, a significant association between
migraine attack duration and severity has been reported
[33]. Similarly, we did not detect any significant
association between seven polymorphisms in
the eNOS gene and migraine with or without aura.
However, when the results are evaluated alongside
clinical findings, we hypothesize that the TT genotype
in the eNOS rs1799983 gene polymorphism could be
a risk factor in migraine with aura patients who have
headache duration of longer than 24 hours.
Two studies, conducted in Austria and Spain,
reported that there was no significant association between
eNOS rs1800779 and rs1799983 gene polymorphisms
and migraine [2,3] However, our data suggest
that the eNOS rs1799983 gene polymorphism
could have an important role in determining migraine
attack duration and the intensity of these attacks. The
most important aim of migraine treatment should be
the reduction of duration and severity of the attacks. It
has been claimed that treatment plan and medicine selection
should be carried out on that basis. Our results
support the hypothesis that vascular genetic factors
play an important role in migraine pathogenesis. As a
result, the eNOS rs743506, rs2070744, rs180079, and
especially rs1799983 gene polymorphisms could be
a risk factor in the formation of migraine symptoms.
In this respect, we recommend that to clarify the significance
of this gene polymorphism and haplotype
analysis, it is necessary to perform a large scale study
and prospective cohort study with an increased number
of subjects, to more accurately judge the association
of the polymorphism with migraine.
Declaration of Interest. This research backed
by the Trakya University Scientific Research Projects
Unit, Edirne, Turkey. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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