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|Year : 2014 | Volume
| Issue : 1 | Page : 9-14
Investigation of the Rho-kinase 2 gene Thr431Asn polymorphism in migraine
Samiye Uslu Kuzudisli1, Mustafa Yilmaz2, Zeynep Gül3, Seniz Demiryürek4, Remzi Yigiter2, Hakan Bozkurt2, Aylin Akcali2, Münife Neyal2, Cahit Bagci4, Beyhan Cengiz4, Serdar Öztuzcu3, Abdullah T Demiryürek5
1 Department of Neurology, Emine-Bahaeddin Nakiboglu Medical Faculty, Zirve University, Gaziantep, Turkey
2 Department of Neurology, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey
3 Department of Medical Biology, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey
4 Department of Physiology, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey
5 Department of Medical Pharmacology, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey
|Date of Submission||14-Nov-2013|
|Date of Decision||20-Dec-2013|
|Date of Acceptance||31-Jan-2014|
|Date of Web Publication||7-Mar-2014|
Samiye Uslu Kuzudisli
Department of Neurology, Emine-Bahaeddin Nakiboglu Medical Faculty, Zirve University, Gaziantep
Source of Support: None, Conflict of Interest: None
Background: Migraine has a complex etiology determined by genetic and environmental factors, but the molecular mechanisms and genetics of this disease have not yet been fully clarified. Aim: This case/control study was designed to analyze the genotype distributions and allele frequencies for the Rho-kinase 2 (ROCK2) gene Thr431Asn polymorphism among the migraine patients. Materials and Methods: A total of 155 migraine patients and 155 healthy age and sex matched controls were included in this study. Genomic deoxyribonucleic acid from migraine patients and controls was analyzed by real-time polymerase chain reaction. Results: Neither genotype distributions nor the allele frequencies for the Thr431Asn polymorphism showed a significant difference between the groups. In addition, there were no marked differences in genotype and allele frequencies for the migraine without aura and migraine with aura subgroups when compared with control group. Conclusion: This is the first study to show that the ROCK2 gene Thr431Asn polymorphism is not a risk factor for the migraine in the Turkish population.
Keywords: Aura, genotype, migraine, polymorphism, Rho-kinase
|How to cite this article:|
Kuzudisli SU, Yilmaz M, Gül Z, Demiryürek S, Yigiter R, Bozkurt H, Akcali A, Neyal M, Bagci C, Cengiz B, Öztuzcu S, Demiryürek AT. Investigation of the Rho-kinase 2 gene Thr431Asn polymorphism in migraine. Neurol India 2014;62:9-14
|How to cite this URL:|
Kuzudisli SU, Yilmaz M, Gül Z, Demiryürek S, Yigiter R, Bozkurt H, Akcali A, Neyal M, Bagci C, Cengiz B, Öztuzcu S, Demiryürek AT. Investigation of the Rho-kinase 2 gene Thr431Asn polymorphism in migraine. Neurol India [serial online] 2014 [cited 2020 May 29];62:9-14. Available from: http://www.neurologyindia.com/text.asp?2014/62/1/9/128241
| » Introduction|| |
Migraine is a common neurological disorder , and affects approximately 12% of the population, predominantly females.  Many migraineurs experience frequent and severe attacks that cause significant disability and impairment of normal daily functioning.  The International Headache Society (IHS) classifies migraine into two main subtypes; migraine with aura (MA) and migraine without aura (MO).  Twin studies have shown that migraine has a significant genetic component, with first-degree relatives of migraineurs with increased risk for the disease.  Due to the genetic heterogeneity of migraine further complicated by environmental factors, the pathophysiological mechanisms are not yet completely understood.
Rho-kinase is a serine/threonine kinase which is activated by the small G protein Rho. Rho-kinase has 2 isoforms; ROCK1 and ROCK2. Rho and Rho-kinase are highly expressed in the nervous system, implying important roles for these proteins in neuron and/or glial cells.  Rho/Rho-kinase pathway may participate in a wide range of fundamental cellular functions within the central nervous system (CNS), such as synaptic vesicle recycling, exocytosis, endocytosis, cell morphology, motility, adhesion, migration and apoptosis. ,, Several other functions have also been attributed to Rho/Rho-kinase signaling within the CNS, including axonal growth,  neurotransmitter release,  pain development, , opening of tight junctions between brain endothelial cells,  formation of branched dendrites,  extension and retraction of neuritis.  It has been reported that Rho-kinase inhibitors may produce beneficial effects in the treatment of cerebral vasospasm after subarachnoid hemorrhage,  and have efficacy in neuropathic and nociceptive pain models.  Rho-kinase inhibition may also be useful in treating chronic pain. 
There has been limited progress in identifying genes for the common forms of migraine. Recent genome-wide association study yielded evidence for weak associations between migraine and 3 single nucleotide polymorphisms (rs2651899, PR domain containing 16, PRDM16; rs10166942, transient receptor potential melastatin 8, TRPM8; and rs11172113 low density lipoprotein receptor-related protein 1, LRP1).  However, the role of Rho-kinase in migraine is not established. Thr431Asn polymorphism of the ROCK2 gene has relatively high minor allele frequency in various populations and has been widely studied studied. ,,, Until now, no report of Thr431Asn polymorphism of the ROCK2 gene in patients with migraine has been published. Therefore, the purpose of this study was to test a possible association between ROCK2 gene Thr431Asn polymorphism and migraine in a Turkish population.
| » Materials and Methods|| |
The study group consisted of 155 patients with migraine and 155 age and sex matched unrelated healthy volunteers with no previous or current history of migraine, control group. Typical migraine individuals were diagnosed as having either MA or MO through interview by neurologists. Questionnaires prepared using strict the IHS guidelines were used.  Demographic details and clinical data such as migraine type and frequency, past medical history, hypertension history, concomitant drug history and relevant family history were collected. The results of the cranial magnetic resonance imaging, computed brain tomography and biochemical laboratory tests for all patients were also evaluated. The control group was also interviewed and subjected to a questionnaire by specialist neurologists. Control subjects had no clinical evidence or family history of migraine or other neurological diseases and no history of diabetes mellitus, coronary artery disease, hypertension, inflammatory and autoimmune diseases, or genetic disorders. Participants were all of Caucasian origin and from the same geographical area (Southeastern Turkey). All migraine patients were registered at the outpatient clinic of the Neurology Department at Gaziantep University, Medical Faculty. In all subjects medical examinations were carried out and venous blood samples were taken for molecular analysis of ROCK2 gene polymorphism. This case-control study was approved by the local Ethics Committee and it was conducted in accordance with the guidelines in the declaration of Helsinki. The demographic characteristics of the study population are shown in [Table 1].
Blood samples and deoxyribonucleic acid isolation
Venous blood samples from all study participants were collected in ethylenediaminetetraacetic acid-containing tubes. Immediately after collection, whole blood was stored at - 20°C until use. Genomic DNA was extracted from whole blood using with salting-out method and stored at - 20°C. 
Thr431Asn (rs2230774) polymorphism located on the exon 10 of the ROCK2 gene and analysis of this polymorphism was performed by real-time polymerase chain reaction (PCR) as described previously.  LightCycler Instrument (Roche Diagnostics GmbH, Mannheim, Germany) was used for real-time PCR. The primers used were 5'- ATGAAACTAAAATAACTACAGCAG-3' (forward) and 5'- AACTTGAATAAAACAGCACATAG-3' (reverse). Hybridization probes used were 5'- TTGTATGGAATCATTTTCTCTACAAGAT-FL (Probe 1) and 5'- LC640-AGAGTCACTTAATAAT CTACATGGAGGGG-PH (Probe 2). Probes were designed by TIB (Molbiol, Berlin, Germany). The LightCycler Instrument measures the emitted fluorescence of the LightCycler-red 640. The hybridization probes in combination with the LightCycler FastStart DNA Master HybProbe Kit (Roche Diagnostics GmbH, Mannheim, Germany) were used to determine the genotype by using a melting curve analysis after the amplification cycles were completed.
All related gene regions were amplified in 20 μl PCR capillary tubes. After preparation of the master mixture, 18 μl of the reaction mixture and 2 μl (approximately 40 ng) of genomic DNA or control template were added to each LightCycler capillary tube. For negative control, PCR grade water was added instead of template. The cycling program was carried out after a denaturation step at 95°C for 10 min through 50 cycles (denaturation at 95°C for 10 s, annealing at 50°C for 10 s, extension at 72°C for 15 s), with a maximum ramp rate of 20 o C/s. Fluorescence was measured at the end of the annealing period of each cycle to monitor amplification. After amplification was complete, a final melting curve was recorded by 90 s denaturation at 95°C followed by a continuous temperature increase from 40°C to 85°C in increments of 0.2°C/s. The fluorescence signal was converted to a melting peak by plotting the negative derivative of the fluorescence with respect to temperature versus temperature (−dF/dT vs. T). The resulting melting peak allowed discrimination among the homozygous as well as the heterozygous genotypes.
Results are expressed as the mean ± standard deviation or percentage. Statistical analysis was performed using GraphPad Instat (version 3.05, GraphPad Software Inc., San Diego, CA, USA). Polymorphisms were tested for deviation from Hardy-Weinberg equilibrium by comparing the observed and expected genotype frequencies using the Chi-square test. For calculation of the significance of differences in genotype and allele frequencies, the Chi-square test or Fisher's exact test were used; and for comparisons of the differences between mean values of two groups, the unpaired Student's t-test was used. The odds ratio at a 95% confidence interval was calculated as an indication of disease risk. P < 0.05 (2-tailed probability) were considered to be statistically significant. Sample size was estimated by using a power calculation based on 15% increase in migraine patient genotype frequencies. It was estimated that at least 151 patients would be required to detect a significant difference between control and patient groups at 80% power level (α = 0.05).
| » Results|| |
Of the 155 patient group 15 patients had MA and 140 patients MO. There were no significant differences between patient and control groups in terms of mean age and sex distribution [Table 1]. Both the migraine population (P = 0.5666) and the control population (P = 0.9988) were found to be in Hardy-Weinberg equilibrium. The distribution of Thr/Thr, Thr/Asn and Asn/Asn genotypes of ROCK2 gene was 29.0%, 53.6% and 17.4% in migraine patients compared with 27.7%, 49.7% and 22.6% in the controls [Table 2]. No statistically significant differences were found between groups in allele frequency and genotype distribution [Table 2]. There were also no significant differences in genotype or allele frequencies between MA and controls, or MO and controls [Table 2]. There was also no significant association between controls and migraine in term of gender [Table 3]. There was no impact of Thr431Asn polymorphism on family history of migraine, migraine attacks frequency, hypertension history or migraine subtypes [Table 4].
|Table 3: Distribution of Thr431Asn polymorphism according to gender in control and patient groups|
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| » Discussion|| |
To the best of our knowledge, this is the first study of the relationship between ROCK2 gene Thr431Asn polymorphism and migraine. No statistically significant association between migraine and the studied ROCK2 gene Thr431Asn polymorphism was demonstrated. Our findings suggest that the ROCK2 gene Thr431Asn polymorphism was not involved in the migraine pathogenesis for our Turkish population.
Migraine involves widespread changes in brain function and connectivity. The vasculature appears to play a special role in migraine. For example, migraineurs carry an approximately two-fold increased risk for ischemic stroke compared to non-migraineurs  and altered vascular reactivity can be found among young migraineurs even in the absence of other disorders.  These findings may be linked to oxidative stress causing endothelial dysfunction.  It has been demonstrated that patients with chronic migraine have endothelial dysfunction and increase in the arterial stiffness.  These findings suggest that migraine attacks are associated with endothelial dysfunction [Figure 1]. ROCK also plays a role in endothelial dysfunction.  Rho/Rho-kinase activation plays a central role in impaired production of nitric oxide (NO) due to multiple actions on endothelial nitric oxide synthase (eNOS). Rho/Rho-kinase activation decreases eNOS expression by reducing the eNOS messenger ribonucleic acid stability  and has been associated with the mechanism of thrombus formation and vascular inflammation.  Collectively, these findings indicate that Rho-kinase may involve in the endothelial dysfunction observed in migraine [Figure 1].
|Figure 1: Potential mechanism of Rho-kinase (ROCK) in migraine. Migraine is associated with endothelial dysfunction, defi ned as an imbalance between endothelium-derived relaxing factors and endothelium-derived constricting factors, is induced by various factors including reactive oxygen species and endothelin-1. The actions of these factors involve abnormal function of endothelial cells and smooth muscle cells (SMC) with altered vascular contraction through RhoA/ROCK pathway activation. This ultimately leads to endothelial barrier dysfunction/edema and enhanced SMC contractility. In addition, the RhoA/ROCK pathway plays a central role in impaired production of the nitric oxide due to reduction of constitutive endothelial nitric oxide synthase (eNOS) phosphorylation and down regulation of eNOS messenger ribonucleic acid stability. RhoA/ROCK pathway has also been also associated with the vascular infl ammation. The dimeric structure is essential for normal in vivo function of ROCK. The Thr431Asn polymorphism lies immediately carboxyl-terminal to the start of the putative coiled-coil region and may decrease ROCK2/ROCK2 parallel homodimerization and Rho binding|
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The etiology of migraine is not well-understood. On the basis of genetic and epidemiological evidence, it has been suggested that changes in blood vessels, hypoperfusion disorders and cerebral microembolism can cause neurovascular dysfunction and evoke cortical spreading depression (CSD), an event that is widely thought to underlie aura symptoms.  CSD, a slowly propagating wave of neuronal and glial cell depolarization spreading over cortex, is thought to underlie the aura and can activate trigeminal nociceptors. , CSD is sometimes triggered by brief hypoxic-ischemic episodes, including endothelin-1 (ET-1)-induced vasospasm and microinfarcts or aneurismal subarachnoid hemorrhage,  as well as in vitro brief hypoxia and mitochondrial inhibition. , Dreier et al.  showed that the vasoconstrictive peptide ET-1 induced change characteristic of CSD in the rat cortex suggesting that a vascular mediated event act as a trigger for CSD. It is known that Rho/Rho-kinase signaling pathway involves to ET-1-induced contraction in the rabbit basilar artery.  Inhibition of Rho/Rho-kinase signaling also offers neuroprotective therapy against post-ischemic neural damage, by inhibiting leukocyte infiltration and endothelial disarrangement. 
The release of inflammatory mediators such as cytokines and mast cells following CSD, may further promote and sustain the activation and sensitization of meningeal nociceptors, inducing the persistent headache characterized in migraine.  Mast cells release proteases and inflammatory mediators, including tumor necrosis factor (TNF)-α and interleukin (IL-6) upon exposure to sensory neuropeptides.  A "neurogenic inflammation" appears to be a key mechanism in causing the migraine headache by activating the trigeminal system.  Plasma levels of TNF-α have been reported to increase during a migraine attack.  TNF-α affects the CNS through cytokines, such as IL-6, release from neurons, astrocytes and microglia. It has been demonstrated that Rho-kinase regulates the TNF-α-induced IL-6 release in C6 glioma cells.  Therefore, Rho-kinase inhibitor may be considered to be a new clinical candidate for the treatment of CNS disorders in addition to cerebral vasospasms.
Migraine prevalence is three- to four-fold higher in women than men.  Furthermore, some women suffer from migraine attacks presenting at specific times during the menstrual cycle or experience changing patterns of attacks during pregnancy or after menopause.  In addition, changes in estrogen levels can trigger migraine attacks.  Females were 3.4-fold higher than men in our study. We have investigated the effects of gender on the genotype and allele distribution of the Thr431Asn polymorphism, but no association was found.
Rho-kinases exist as dimers by parallel association at the coiled-coil domain and the dimerized kinase domain of Rho-kinase appears to be in an active conformation in the absence of phosphorylation.  The Thr431Asn polymorphism lies immediately carboxyl-terminal to the start of the putative coiled-coil region and encodes an amino acid substitution in the predicted coiled-coil domain of the protein, which is associated with ROCK2/ROCK2 parallel homodimerization and Rho binding. Since the dimeric structure is essential for normal in vivo function,  changes in the coiled-coil region could be hypothesized to effect dimerization, Rho binding and thereby ROCK activation and phosphorylation of its substrates.
Our study suggests that there is no association between Thr431Asn polymorphism and migraine. Our data showed that the ROCK2 gene may not be a susceptible gene in Turkish patients with migraine. However, analysis of other variations in this gene for association with migraine would be helpful in elucidating the involvement of ROCK2 gene in migraine pathogenesis. Future genetic studies in larger populations and expression analysis are required to clarify the role of ROCK2 gene in migraine susceptibility. Further studies are also required to verify these findings in different ethnic groups.
| » Acknowledgment|| |
This study was supported by a project (BAP TF.09.19) from the University of Gaziantep.
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[Table 1], [Table 2], [Table 3], [Table 4]