Skip to main content

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

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.

This is a preview of subscription content, access via your institution.

References

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

    PubMed  Article  Google Scholar 

  2. 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.

    PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  4. 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.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  6. 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.

    PubMed  Article  Google Scholar 

  7. 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.

    PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  9. 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.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  11. 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.

    CAS  PubMed  Article  Google Scholar 

  12. 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.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  14. 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.

    CAS  PubMed  Article  Google Scholar 

  15. 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.

    CAS  PubMed  Article  Google Scholar 

  16. 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.

    CAS  PubMed  Article  Google Scholar 

  17. 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 

  18. 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.

    PubMed Central  PubMed  Article  Google Scholar 

  19. 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.

    CAS  PubMed  Article  Google Scholar 

  20. 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 

  21. 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 

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

    CAS  PubMed  Article  Google Scholar 

  23. 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 

  24. 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.

    CAS  Article  Google Scholar 

  25. 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.

    CAS  Article  Google Scholar 

  26. 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.

    PubMed  Article  Google Scholar 

  27. 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.

    PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  29. 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.

    PubMed  Article  Google Scholar 

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

    PubMed Central  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  32. 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.

    CAS  PubMed  Article  Google Scholar 

  33. 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.

    CAS  PubMed  Article  Google Scholar 

  34. 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.

    CAS  PubMed  Article  Google Scholar 

  35. 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.

    PubMed Central  PubMed  Article  Google Scholar 

  36. 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 

  37. 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.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

  39. 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.

    PubMed  Article  Google Scholar 

  40. 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 

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

    PubMed  Article  Google Scholar 

  42. 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.

    CAS  PubMed  Article  Google Scholar 

  43. 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.

    PubMed Central  PubMed  Article  Google Scholar 

  44. 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.

    CAS  Article  Google Scholar 

  45. 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.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

Download references

Acknowledgments

We especially wish to thank the participants in this study for their devoted participation.

Conflict of interest

The authors have no conflicts of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Recep Eröz.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Keywords

  • eNOS polymorphism
  • Migraine
  • Clinical parameters
  • Aura
  • Homocysteine