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Association of Endothelial Nitric Oxide Synthase Gene Polymorphisms (894G/T, −786T/C, G10T) and Clinical Findings in Patients with Migraine

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Abstract

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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References

  • Bigal, M. E., Liberman, J. N., & Lipton, R. B. (2006). Obesity and migraine: a population study. Neurology, 66, 545–550.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Brennan, K. C., & Charles, A. (2010). An update on the blood vessel in migraine. Current Opinion in Neurology, 23, 266–274.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Crawford, D. C., & Nickerson, D. A. (2005). Definition and clinical importance of haplotypes. Annual Review of Medicine, 56, 303–320.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Ducros, A., Tournier-Lasserve, E., & Bousser, M. G. (2002). The genetics of migraine. Lancet Neurology, 1, 285–293.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Ferrari, M. (1998). Migraine. The Lancet, 351, 1043–1051.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Goadsby, P. J. (1997). Current concepts of the pathophysiology of migraine. Neurologic Clinics, 15, 27–42.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Maher, B. H., & Griffiths, L. R. (2011). Identification of molecular genetic factors that influence migraine. Molecular Genetics and Genomics, 285, 433–446.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Olesen, J. (2010). Nitric oxide-related drug targets in headache. Neurotherapeutics, 7, 183–190.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Peterlin, B. L., Rapoport, A. M., & Kurth, T. (2010). Migraine and obesity: Epidemiology, mechanisms, and implications. Headache, 50, 631–648.

    Article  PubMed Central  PubMed  Google Scholar 

  • Pietrobon, D., & Striessnig, J. (2003). Neurobiology of migraine. Nature Reviews Neuroscience, 4, 386–398.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tietjen, E. G. (2007). Migraine and ischaemic heart disease and stroke: Potential mechanisms and treatment implications. Cephalalgia, 27, 981–987.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Vanmolkot, F. H., Van Bortel, L. M., & de Hoon, J. N. (2007). Altered arterial function in migraine of recent onset. Neurology, 68, 1563–1570.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

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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Correspondence to Recep Eröz.

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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

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  • DOI: https://doi.org/10.1007/s12017-014-8311-0

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