Migraine is a common neurological disorder characterized by recurrent attacks, unilateral head pain, and related symptoms. The aim of this study was to investigate three endothelial nitric oxide synthase (eNOS) polymorphisms in 176 patients with migraine and 123 healthy individuals. Clinical and biochemical parameters were investigated. Genetic analysis was performed using the polymerase chain reaction–restriction fragment length polymorphism method. The differences between migraine cases and the control group were significant for two polymorphisms (−786T/C and 894G/T) (p = 0.000). Homocysteine and body mass index (BMI) were significantly higher in the migraine group than in the control group (p = 0.001 and p = 0.000). The relation between −786T/C genotype and BMI and allodynia was significant. TC heterozygotes and CC homozygotes were significantly higher in the migraine group than in the control group (OR 2.843 and 95 % CI 1.681–4.808 and OR 3.729 and 95 % CI 1.784–7.792, respectively). The 894G/T genotype was correlated with BMI, pain intensity, age at the onset of migraine, nausea, tension, compression, and allodynia. For this polymorphism, GT heterozygotes and TT homozygotes were significantly higher in the migraine group than in the control group (OR 3.027 and 95 % CI 1.830–5.008 and OR 3.221 and 95 % CI 1.223–8.484, respectively). The G10T genotype was correlated with attack duration and age at the onset of migraine (p = 0.008 and p = 0.040). eNOS polymorphisms may be useful markers for assessing migraine risk and clinical diagnosis.
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Bigal, M. E., Liberman, J. N., & Lipton, R. B. (2006). Obesity and migraine: a population study. Neurology, 66, 545–550.
Borroni, B., Rao, R., Liberini, P., Venturelli, E., Cossandi, M., Archetti, S., et al. (2006). Endothelial nitric oxide synthase (Glu298Asp) polymorphism is an independent risk factor for migraine with aura. Headache, 46, 1575–1579.
Brennan, K. C., & Charles, A. (2010). An update on the blood vessel in migraine. Current Opinion in Neurology, 23, 266–274.
Colson, N. J., Lea, R. A., Sharon, Q., & Griffiths, L. R. (2006). The role of vascular and hormonal genes in migraine susceptibility. Molecular Genetics and Metabolism, 88, 107–113.
Crawford, D. C., & Nickerson, D. A. (2005). Definition and clinical importance of haplotypes. Annual Review of Medicine, 56, 303–320.
De Fusco, M., Marconi, R., Silvestri, L., Atorino, L., Rampoldi, L., Morgante, L., et al. (2003). Haploinsufficiency of ATP1A2 encoding the Na+/K+pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nature Genetics, 33, 192–196.
Di Rosa, G., Attinà, S., Spanò, M., Ingegneri, G., Sgrò, D. L., Pustorino, G., et al. (2007). Efficacy of folic acid in children with migraine, hyperhomocysteinemia and MTHFR polymorphisms. Headache, 47, 1342–1344.
Ducros, A., Tournier-Lasserve, E., & Bousser, M. G. (2002). The genetics of migraine. Lancet Neurology, 1, 285–293.
Fernandez, F., Colson, N. J., & Griffiths, L. R. (2007). Pharmacogenetics of migraine: Genetic variants and their potential role in migraine therapy. Pharmacogenomics, 8, 609–614.
Ferrari, M. (1998). Migraine. The Lancet, 351, 1043–1051.
Ford, E. S., Li, C., Pearson, W. S., Zhao, G., Strine, T. W., & Mokdad, A. H. (2008). Body mass index and headaches: Findings from a national sample of US adults. Cephalalgia, 28, 1270–1276.
Gkaliagkousi, E., Douma, S., Zamboulis, C., & Ferro, A. (2009). Nitric oxide dysfunction in vascular endothelium and platelets: Role in essential hypertension. Journal of Hypertension, 27, 2310–2320.
Goadsby, P. J. (1997). Current concepts of the pathophysiology of migraine. Neurologic Clinics, 15, 27–42.
Goncalves, F. M., Martins-Oliveira, A., Speciali, J. G., Izidoro-Toledo, T. C., Luizon, M. R., Dach, F., et al. (2010). Vascular endothelial growth factor genetic polymorphisms and haplotypes in women with migraine. DNA and Cell Biology, 29, 357–362.
Goncalves, F. M., Martins-Oliveira, A., Speciali, J. G., Luizon, M. R., Izidoro-Toledo, T. C., Silva, P. S., et al. (2011). Endothelial nitric oxide synthase haplotypes associated with aura in patients with migraine. DNA and Cell Biology, 30, 363–369.
Goncalves, F. M., Luizon, M. R., Speciali, J. G., Martins-Oliveira, A., Dach, F., & Tanus-Santos, J. E. (2012). Interaction among nitric oxide (NO)-related genes in migraine susceptibility. Molecular and Cellular Biochemistry, 370, 183–189.
Gruber, H. J., Bernecker, C., Lechner, A., Weiss, S., Wallner-Blazek, M., Meinitzer, A., et al. (2010). Increased nitric oxide stress is associated with migraine. Cephalalgia, 30, 486–492.
Haut, S. R., Bigal, M. E., & Lipton, R. B. (2006). Chronic disorders with episodic manifestations: Focus on epilepsy and migraine. Lancet Neurology, 5, 148–157.
Kurth, T., Gaziano, J. M., Cook, N. R., Logroscino, G., Diener, H. C., & Buring, J. E. (2006). Migraine and risk of cardiovascular disease in women. JAMA, 296, 283–291.
Lovati, C., D’Amico, D., Rosa, S., Suardelli, M., Mailland, E., Bertora, P., et al. (2007). Allodynia in different forms of migraine. Neurological Sciences, 28(2), 220–221.
MacClellan, L. R., Howard, T. D., Cole, J. W., Stine, O. C., Giles, W. H., O’Connell, J. R., et al. (2009). Relation of candidate genes that encode for endothelial function to migraine and stroke: The Stroke Prevention in Young Women study. Stroke, 40, 550–557.
Maher, B. H., & Griffiths, L. R. (2011). Identification of molecular genetic factors that influence migraine. Molecular Genetics and Genomics, 285, 433–446.
Marsden, P. A., Heng, H. H., Scherer, S. W., Stewart, R. J., Hall, A. V., Shi, X. M., et al. (1993). Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. Journal of Biological Chemistry, 268, 17478–17488.
Martins-Oliveira, A., Speciali, J. G., Dach, F., Marcaccini, A. M., Goncalves, F. M., Gerlach, R. F., et al. (2009). Different circulating metalloproteinases profiles in women with migraine with and without aura. Clinica Chimica Acta, 408, 60–64.
Metzger, I. F., Sertorio, J. T., & Tanus-Santos, J. E. (2007). Modulation of nitric oxide formation by endothelial nitric oxide synthase gene haplotypes. Free Radical Biology & Medicine, 43, 987–992.
Metzger, I. F., Ishizawa, M. H., Rios-Santos, F., Carvalho, W. A., & Tanus-Santos, J. E. (2010). Endothelial nitric oxide synthase gene haplotypes affect nitrite levels in black subjects. The Pharmacogenomics Journal, 11, 393–399.
Mulder, E. J., Van Baal, C., Gaist, D., Kallela, M., Kaprio, J., Svensson, D. A., et al. (2003). Genetic and environmental influences on migraine: A twin study across six countries. Twin Research, 6, 422–431.
Olesen, J. (2010). Nitric oxide-related drug targets in headache. Neurotherapeutics, 7, 183–190.
Oterino, A., Toriello, M., Valle, N., Castillo, J., Alonso-Aranz, A., Bravo, Y., et al. (2010). The relationship between homocysteine and genes of folate-related enzymes in migraine patients. Headache, 50, 99–108.
Peterlin, B. L., Rapoport, A. M., & Kurth, T. (2010). Migraine and obesity: Epidemiology, mechanisms, and implications. Headache, 50, 631–648.
Pietrobon, D., & Striessnig, J. (2003). Neurobiology of migraine. Nature Reviews Neuroscience, 4, 386–398.
Sandrim, V. C., Palei, A. C., Cavalli, R. C., Araujo, F. M., Ramos, E. S., Duarte, G., et al. (2008). eNOS haplotypes associated with gestational hypertension or preeclampsia. Pharmacogenomics, 9, 1467–1473.
Sandrim, V. C., Palei, A. C., Sertorio, J. T., Cavalli, R. C., Duarte, G., & Tanus-Santos, J. E. (2010). Effects of eNOS polymorphisms on nitric oxide formation in healthy pregnancy and in pre-eclampsia. Molecular Human Reproduction, 16, 506–510.
Scher, A. I., Terwindt, G. M., Verschuren, W. M., Kruit, M. C., Blom, H. J., Kowa, H., et al. (2006). Migraine and MTHFR C677T genotype in a population-based sample. Annals of Neurology, 59, 372–375.
Schürks, M., Kurth, T., Buring, J. E., & Zee, R. Y. (2009). A candidate gene association study of 77 polymorphisms in migraine. The Journal of Pain, 10, 759–766.
Schürks, M., Zee, R. Y. L., Buring, J. E., & Kurth, T. (2010). MTHFR 677C→T and ACE D/I polymorphisms and migraine attack frequency in women. Cephalalgia, 30, 447–456.
Stamler, J. S., Osborne, J. A., Jaraki, O., Rabbani, L. E., Mullins, M., Singel, D., et al. (1993). Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. Journal of Clinical Investigation, 91, 308–318.
Tietjen, E. G. (2007). Migraine and ischaemic heart disease and stroke: Potential mechanisms and treatment implications. Cephalalgia, 27, 981–987.
Toriello, M., Oterino, A., Pascual, J., Castillo, J., Colas, R., Alonso-Arranz, A., et al. (2008). Lack of association of endothelial nitric oxide synthase polymorphisms and migraine. Headache, 48, 1115–1119.
Tzourio, C., El Amrani, M., Poirier, O., Nicaud, V., Bousser, M. G., & Alperovitch, A. (2001). Association between migraine and endothelin type A receptor (ETA-231 A/G) gene polymorphism. Neurology, 22, 1273–1277.
Vanmolkot, F. H., Van Bortel, L. M., & de Hoon, J. N. (2007). Altered arterial function in migraine of recent onset. Neurology, 68, 1563–1570.
Vasconcellos, V., Lacchini, R., Jacob-Ferreira, A. L., Sales, M. L., Ferreira-Sae, M. C., Schreiber, R., et al. (2010). Endothelial nitric oxide synthase haplotypes associated with hypertension do not predispose to cardiac hypertrophy. DNA and Cell Biology, 29, 171–176.
Wald, D. S., Law, M., & Morris, J. K. (2002). Homocysteine and cardiovascular disease: Evidence on causality from a meta-analysis. BMJ: British Medical Journal, 325, 1202.
Wewers, M. E., & Lowe, N. K. (1990). A critical review of visual analogue scales in the measurement of clinical phenomena. Research in Nursing & Health, 13, 227–236.
Winter, A. C., Berger, K., Buring, J. E., & Kurth, T. (2009). Body mass index, migraine, migraine frequency and migraine features in women. Cephalalgia, 29, 269–278.
We especially wish to thank the participants in this study for their devoted participation.
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The authors have no conflicts of interest.
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Eröz, R., Bahadir, A., Dikici, S. et al. Association of Endothelial Nitric Oxide Synthase Gene Polymorphisms (894G/T, −786T/C, G10T) and Clinical Findings in Patients with Migraine. Neuromol Med 16, 587–593 (2014). https://doi.org/10.1007/s12017-014-8311-0
- eNOS polymorphism
- Clinical parameters