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

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 C1026A 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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