NeuroMolecular Medicine

, 13:167

The 894G > T (Glu298Asp) Variant in the Endothelial NOS Gene and MTHFR Polymorphisms Influence Homocysteine Levels in Patients with Cognitive Decline

  • Nadia Ferlazzo
  • Gaetano Gorgone
  • Daniela Caccamo
  • Monica Currò
  • Salvatore Condello
  • Francesco Pisani
  • Fabrizio Vernieri
  • Paolo Maria Rossini
  • Riccardo Ientile
Original Paper

Abstract

The presence and severity of cerebrovascular pathological findings have been shown to increase the risk and stage of cognitive decline observed in Alzheimer’s disease and vascular dementia. Thus, the modification of vascular risk factors seems useful to reduce the risk of dementia regardless of type. Hyperhomocysteinemia has long been known as a major independent risk factor for vascular dysfunction. In this study, we evaluated the relationships between plasma homocysteine levels and genetic risk factors for hyperhomocysteinemia, i.e., the presence of gene variants for methylenetetrahydrofolate reductase (MTHFR) and endothelial nitric oxide synthase (eNOS) in patients with cognitive impairment. Genotyping for MTHFR C677T and eNOS 894G > T polymorphisms was carried out in 69 patients with probable diagnosis of AD and anamnestic mild cognitive impairment, matched for age and gender with 69 healthy volunteers. Patients with MTHFR TT677 genotype showed higher plasma Hcy levels than controls, even after adjustment for folate levels (P < 0.05). Moreover, Hcy plasma levels were higher in cases than controls for any given eNOS genotype. In particular, the presence of eNOS TT894 genotype in patients with cognitive decline resulted significantly associated with increased plasma Hcy levels when compared with controls having the same genotype or patients having other eNOS genotypes (P = 0.02). These data suggest that both MTHFR C677T and eNOS G894T variants should be regarded as genetic risk factors for hyperhomocysteinemia in patients with cognitive decline.

Keywords

Alzheimer’s disease Cognitive decline Vascular dementia Hyperhomocysteinemia MTHFR eNOS SNPs 

References

  1. Aisen, P. S., Schneider, L. S., Sano, M., Diaz-Arrastia, R., van Dyck, C. H., Weiner, M. F., et al. (2008). Alzheimer disease cooperative study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: A randomized controlled trial. The Journal of the American Medical Association, 300, 1774–1783.CrossRefGoogle Scholar
  2. Babiloni, C., Bosco, P., Ghidoni, R., Del Percio, C., Squitti, R., Binetti, G., et al. (2007). Homocysteine and electroencephalographic rhythms in Alzheimer disease: A multicentric study. Neuroscience, 145, 942–954.PubMedCrossRefGoogle Scholar
  3. Botto, N., Andreassi, M. G., Manfredi, S., Masetti, S., Cocci, F., Colombo, M. G., et al. (2003). Genetic polymorphisms in folate and Hcy metabolism as risk factors for DNA damage. European Journal of Human Genetics, 11, 671–678.PubMedCrossRefGoogle Scholar
  4. Brown, K. S., Kluijtmans, L. A. J., Young, I. S., Woodside, J., Yarnell, J. W. G., McMaster, D., et al. (2003). Genetic evidence that nitric oxide modulates Hcy. The eNOS 894TT genotype is a risk factor for hyperhomocysteinemia. Arteriosclerosis, Thrombosis, and Vascular Biology, 23, 1014–1020.PubMedCrossRefGoogle Scholar
  5. Caccamo, D., Condello, S., Gorgone, G., Crisafulli, G., Belcastro, V., Gennaro, S., et al. (2004). Screening for C677T and A1298C MTHFR polymorphisms in patients with epilepsy and risk of hyperhomocysteinemia. Neuromolecular Medicine, 6, 117–126.PubMedCrossRefGoogle Scholar
  6. Caccamo, D., Gorgone, G., Currò, M., Parisi, G., Di Iorio, W., Menichetti, C., et al. (2007). Effect of MTHFR polymorphisms on hyperhomocysteinemia in levodopa-treated Parkinsonian patients. Neuromolecular Medicine, 9, 249–254.PubMedCrossRefGoogle Scholar
  7. Chrysohoou, C., Panagiotakos, D. B., Pitsavos, C., Antoniades, C., Skoumas, J., Brown, M., et al. (2004). Evidence for association between endothelial nitric oxide synthase gene polymorphism (894G > T) and inflammatory markers: The ATTICA study. American Heart Journal, 148, 733–738.PubMedCrossRefGoogle Scholar
  8. Colombo, M. G., Andreassi, M. G., Paradossi, U., Botto, N., Manfredi, S., Masetti, S., et al. (2002). Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298– > Asp polymorphism) to the presence, extent, and severity of coronary artery disease. Heart, 87, 525–528.PubMedCrossRefGoogle Scholar
  9. Colombo, M. G., Paradossi, U., Andreassi, M. G., Botto, N., Manfredi, S., Masetti, S., et al. (2003). Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery disease. Clinical Chemistry, 49, 389–395.PubMedCrossRefGoogle Scholar
  10. Crawford, F., Freeman, M., Abdullah, L., Schinka, J., Gold, M., Duara, R., et al. (2000). No association between the NOS3 codon 298 polymorphism and Alzheimer’s disease in a sample from the United States. Annals of Neurology, 47, 687.PubMedCrossRefGoogle Scholar
  11. Datta, S., Pal, S. K., Mazumdar, H., Bhandari, B., Bhattacherjee, S., & Pandit, S. (2009). Homocysteine and cerebrovascular accidents. Journal of the Indian Medical Association, 107, 345–346.PubMedGoogle Scholar
  12. Dayal, S., Arning, E., Bottiglieri, T., Böger, R. H., Sigmund, C. D., Faraci, F. M., et al. (2004). Cerebral vascular dysfunction mediated by superoxide in hyperhomocysteinemic mice. Stroke, 35, 1957–1962.PubMedCrossRefGoogle Scholar
  13. Fatini, C., Sofi, F., Gori, A. M., Sticchi, E., Marcucci, R., Lenti, M., et al. (2005). Endothelial nitric oxide synthase −786T > C, but not 894G > T and 4a4b, polymorphism influences plasma Hcy concentrations in persons with normal vitamin status. Clinical Chemistry, 51, 1159–1164.PubMedCrossRefGoogle Scholar
  14. Fuh, J. L. (2010). Homocysteine, cognition and brain white matter hyperintensities. Acta neurologica Taiwanica, 19, 150–152.PubMedGoogle Scholar
  15. Giusti, B., Gori, A. M., Marcucci, R., Sestini, I., Saracini, C., Sticchi, E., et al. (2007). Role of C677T and A1298C MTHFR, A2756G MTR and −786 C/T eNOS gene polymorphisms in atrial fibrillation susceptibility. PLoS One, 2, 495.CrossRefGoogle Scholar
  16. Gorgone, G., Caccamo, D., Pisani, L. R., Currò, M., Parisi, G., Oteri, G., et al. (2009a). Hyperhomocysteinemia in patients with epilepsy: Does it play a role in the pathogenesis of brain atrophy? A preliminary report. Epilepsia, 50, 33–36.PubMedCrossRefGoogle Scholar
  17. Gorgone, G., Ursini, F., Altamura, C., Bressi, F., Tombini, M., Curcio, G., et al. (2009b). Hyperhomocysteinemia, intima-media thickness and C677T MTHFR gene polymorphism: A correlation study in patients with cognitive impairment. Atherosclerosis, 206, 309–313.PubMedCrossRefGoogle Scholar
  18. Guidi, I., Galimberti, D., Venturelli, E., Lovati, C., Del Bo, R., Fenoglio, C., et al. (2005). Influence of the Glu298Asp polymorphism of NOS3 on age at onset and homocysteine levels in AD patients. Neurobiology of Aging, 26, 789–794.PubMedCrossRefGoogle Scholar
  19. Heil, S. G., Den Heijer, M., Ven Der Rijt-Pisa, B. J. M., Kluijtmans, L. A. J., & Blom, H. J. (2004). The 894G > T variant of endothelial nitric oxide synthase (eNOS) increases the risk of recurrent venous thrombosis through interaction with elevated homocysteine levels. Journal of Thrombosis and Haemostasis, 2, 750–753.PubMedCrossRefGoogle Scholar
  20. Higuchi, S., Ohta, S., Matsushita, S., Matsui, T., Yuzuriha, T., Urakami, K., et al. (2000). NOS3 polymorphism not associated with Alzheimer’s disease in Japanese. Annals of Neurology, 48, 685.PubMedCrossRefGoogle Scholar
  21. Hu, L., & Bentler, P. M. (1999). Cutoff criteria for fit indexes in covariance structure analyses: Conventional criteria versus new alternatives. Structural Equation Modeling, 6, 1–55.CrossRefGoogle Scholar
  22. Iadecola, C., & Davisson, R. L. (2008). Hypertension and cerebrovascular dysfunction. Cell Metabolism, 7, 476–484.PubMedCrossRefGoogle Scholar
  23. Ientile, R., Curro’, M., Ferlazzo, N., Condello, S., Caccamo, D., & Pisani, F. (2010). Homocysteine, vitamin determinants and neurological diseases. Frontiers in Bioscience, 2, 359–372.CrossRefGoogle Scholar
  24. Kalaria, R. (2002). Similarities between Alzheimer’s disease and vascular dementia. Journal of the Neurological Sciences, 15, 29–34.CrossRefGoogle Scholar
  25. Kerkeni, M., Addad, F., Chauffert, M., Myara, A., Ben Farhat, M., Miled, A., et al. (2006). Hyperhomocysteinemia, endothelial nitric oxide synthase polymorphism, and risk of coronary artery disease. Clinical Chemistry, 52, 53–58.PubMedCrossRefGoogle Scholar
  26. Khachaturian, A. S., Zandi, P. P., Lyketsos, C. G., Hayden, K. M., Skoog, I., Norton, M. C., et al. (2006). Antihypertensive medication use and incident Alzheimer disease: The Cache County Study. Archives of Neurolology, 63, 686–692.CrossRefGoogle Scholar
  27. Kuzkaya, N., Weissmann, N., Harrison, D. G., & Dikalov, S. (2003). Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: Implications for uncouplingendothelial nitric-oxide synthase. The Journal of Biological Chemistry, 278, 22546–22554.PubMedCrossRefGoogle Scholar
  28. Laukka, E. J., Fratiglioni, L., & Bäckman, L. (2010). The influence of vascular disease on cognitive performance in the preclinical and early phases of Alzheimer’s disease. Dementia and Geriatric Cognitive Disorders, 29, 498–503.PubMedCrossRefGoogle Scholar
  29. Launer, L. J. (2002). Demonstrating the case that AD is a vascular disease: Epidemiologic evidence. Ageing Research Reviews, 1(1), 61–67.PubMedCrossRefGoogle Scholar
  30. Marlatt, M. W., Lucassen, P. J., Perry, G., Smith, M. A., & Zhu, X. (2008). Alzheimer’s disease: Cerebrovascular dysfunction, oxidative stress, and advanced clinical therapies. Journal of Alzheimer’s Disease, 15, 199–210.PubMedGoogle Scholar
  31. Mattson, M. P., & Shea, T. B. (2003). Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends in Neurosciences, 26, 137–146.PubMedCrossRefGoogle Scholar
  32. Middleton, L. E., & Yaffe, K. (2009). Promising strategies for the prevention of dementia. Archives of Neurology, 66, 1210–1215.PubMedCrossRefGoogle Scholar
  33. Monastero, R., Cefalù, A. B., Camarda, C., Buglino, C. M., Mannino, M., Barbagallo, C. M., et al. (2003). No association between Glu298Asp endothelial nitric oxide synthase polymorphism and Italian sporadic Alzheimer’s disease. Neuroscience Letters, 341, 229–232.PubMedCrossRefGoogle Scholar
  34. Ott, M., Gogvadze, V., Orrenius, S., & Zhivotovsky, B. (2007). Mitochondria, oxidative stress and cell death. Apoptosis, 12, 913–922.PubMedCrossRefGoogle Scholar
  35. Oudi, M. E., Aouni, Z., Mazigh, C., Khochkar, R., Gazoueni, E., Haouela, H., et al. (2010). Homocysteine and markers of inflammation in acute coronary syndrome. Experimental and Clinical Cardiology, 15, 25–28.Google Scholar
  36. Owuor, E. D., & Kong, A. N. (2002). Antioxidants and oxidants regulated signal transduction pathways. Biochemical Pharmacology, 64, 765–770.PubMedCrossRefGoogle Scholar
  37. Pacher, P., Beckman, J. S., & Liaudet, L. (2007). Nitric oxide and peroxynitrite in health and disease. Physiological Reviews, 87, 315–424.PubMedCrossRefGoogle Scholar
  38. Peila, R., White, L. R., Masaki, K., Petrovitch, H., & Launer, L. J. (2006). Reducing the risk of dementia: Efficacy of long-term treatment of hypertension. Stroke, 37, 1165–1170.PubMedCrossRefGoogle Scholar
  39. Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J., Tangalos, E. G., & Kokmen, E. (1999). Mild cognitive impairment: Clinical characterization and outcome. Archives of Neurology, 56, 303–308.PubMedCrossRefGoogle Scholar
  40. Sánchez-Guerra, M., Combarros, O., Alvarez-Arcaya, A., Mateo, I., Berciano, J., González-García, J., et al. (2001). The Glu298Asp polymorphism in the NOS3 gene is not associated with sporadic Alzheimer’s disease. Journal of Neurology, Neurosurgery and Psychiatry, 70, 566–567.CrossRefGoogle Scholar
  41. Seshadri, S., Beiser, A., Selhub, J., Jacques, P. F., Rosenberg, I. H., D’Agostino, R. B., et al. (2002). Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. New England Journal of Medicine, 346, 476–483.PubMedCrossRefGoogle Scholar
  42. Sharma, P., Senthilkumar, R. D., Brahmachari, V., Sundaramoorthy, E., Mahajan, A., Sharma, A., et al. (2006). Mining literature for a comprehensive pathway analysis: A case study for retrieval of homocysteine related genes for genetic and epigenetic studies. Lipids in Health and Disease, 5, 1.PubMedCrossRefGoogle Scholar
  43. Tesauro, M., Thompson, W. C., Rogliani, P., Qi, L., Chaudhary, P. P., & Moss, J. (2000). Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: Cleavage of proteins with aspartate vs. glutamate at position 298. Proceedings of the National Academy of Science, 97, 2832–2835.CrossRefGoogle Scholar
  44. Topal, G., Brunet, A., Millanvoye, E., Boucher, J. L., Rendu, F., Devynck, M. A., et al. (2004). Homocysteine induces oxidative stress by uncoupling of no synthase activity through reduction of tetrahydrobiopterin. Free Radical Biology and Medicine, 36, 1532–1541.PubMedCrossRefGoogle Scholar
  45. Veldman, B. A., Spiering, W., Doevendans, P. A., Vervoort, G., Kroon, A. A., & de Leeuw, P. W. (2002). The Glu298Asp polymorphisms of the eNOS gene as a determinant of the baseline production of nitric oxide. Journal of Hypertension, 20, 2023–2027.PubMedCrossRefGoogle Scholar
  46. Winkelmayer, W. C., Huber, A., Wagner, O. F., Horl, W. H., Sunder Plassmann, G., & Fodinger, M. (2005). Associations between MTHFR 1793G > A and plasma total homocysteine, folate, and vitamin B in kidney transplant recipients. Kidney International, 67, 1980–1985.PubMedCrossRefGoogle Scholar
  47. Zambrzycka, A., Cakała, M., & Kamińska, M. (2003). Transition metal ions significantly decrease phospholipase C activity degrading phosphatidylinositol-4,5-bisphosphate in the brain cortex. Polish Journal of Pharmacology, 55, 915–917.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Nadia Ferlazzo
    • 1
  • Gaetano Gorgone
    • 2
  • Daniela Caccamo
    • 1
  • Monica Currò
    • 1
  • Salvatore Condello
    • 1
  • Francesco Pisani
    • 3
  • Fabrizio Vernieri
    • 4
  • Paolo Maria Rossini
    • 4
  • Riccardo Ientile
    • 1
  1. 1.Department of Biochemical, Physiological and Nutritional SciencesUniversity of MessinaMessinaItaly
  2. 2.Department of Clinical and Experimental Medicine, Medical SchoolUiniversity of CatanzaroCatanzaroItaly
  3. 3.Department of NeurosciencesUniversity of MessinaMessinaItaly
  4. 4.Clinical Neurology (P.M.R.)University Campus Bio-MedicoRomeItaly

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