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In recent years, the activity of the regulatory enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), which influences migraine attacks, has been intensely discussed. In particular, this genetic risk factor, together with diagnostic and symptomatic characteristics, can predispose to Migraine. The present study assessed the functional polymorphism and its prevalence of MTHFR (C677T and A1298C) gene variants among 186 Migraineurs (116 (MA) and 70 (MWA)) compared with 152 healthy individuals. The incidence of (MTHFR 677 T and MTHFR 1298C) allele were significantly higher in Migraineurs (30.6%, 51.3%). Genotypes T677T and C1298C have been associated to induce migraine attacks (Odds Ratio (OR) = 3.53; 95% Confidence Interval (CI) = 1.18–27.86; p-value = 0.01) and (OR = 7.19; 95%, CI = 0.19–27.41; p = 0.01) respectively. Similarly, mutant interaction analysis was performed, and it was found that both genotypes were more closely associated with Migraine. Interactions of both variants had a higher risk for causing migraine in the genotypes CCAA (p = 0.02), CCCC (p = 0.05), CTAA (p = 0.03), and TTAC (p = 0.02). Patients having MA are more susceptible to genotypes (CCAA, CTAA, and TTAC), while MWA was more affected by (CCCC p = 0.05). Altogether, it could be concluded that folate metabolism plays an essential role in the onset of Migraine. Further studies involving larger populations may pave the way to clarify genotype-phenotype relationships.
T. J. Steiner, L. J. Stovner, and G. L. Birbeck, “Migraine: The seventh disabler,” The Journal of Headache and Pain, vol. 14, no. 1, p. 1, Dec. 2013.
D. Millstine, C. Y. Chen, and B. Bauer, “Complementary and integrative medicine in the management of headache,” BMJ Journal, vol. 357, p. j1805, May 2017.
P. Klinkwan, C. Kongmaroeng, S. Muengtaweepongsa, and W. Limtrakarn, “The effectiveness of mirror therapy to upper extremity rehabilitation in acute stroke patients,” Applied Science and Engineering Progress, to be published, doi: 10.14416/j.asep. 2021.05.002.
S. T. Anne Sahithi, T. Muthu, and R. Saraswathy, “Migraine: Update and future perspectives,” International Journal of Nutrition, Pharmacology, Neurological Diseases, vol. 10, no. 4, pp. 179– 187, 2020.
J. Olesen, “Headache classification committee of the International Headache Society (IHS) the international classification of headache disorders, 3rd edition,” Cephalalgia, vol. 38, no. 1, pp. 1–211, Jan. 2018, doi: 10.1177/0333102417738202.
J. Olesen, “The international classification of headache disorders,” in Headache. London, England: International Headache Society, 2008, pp. 691–693.
P. Rizzoli and W. J. Mullally, “Headache,” The American Journal of Medicine, vol. 131, no. 1, pp. 17–24, Jan. 2018.
A. Ducros, E. Tournier-Lasserve, and M.-G. Bousser, “The genetics of migraine,” The Lancet Neurology, vol. 1, no. 5, pp. 285–293, Sep. 2002.
J. M. Hansen, R. B. Lipton, D. W. Dodick, S. D. Silberstein, J. R. Saper, S. K. Aurora, P. J. Goadsby, and A. Charles, “Migraine headache is present in the aura phase: A prospective study,” Neurology, vol. 79, no. 20, pp. 2044–2049, 2012.
M. F. P. Peres, J. P. P. Mercante, P. R. Tobo, H. Kamei, and M. E. Bigal, “Anxiety and depression symptoms and migraine: A symptom-based approach research,” Journal of Headache and Pain, vol. 18, no. 1, p. 37, Mar. 2017.
R. E. Shapiro and P. J. Goadsby, “The long drought: The dearth of public funding for headache research,” Cephalalgia, vol. 27, no. 9, pp. 991–994, Sep. 2007.
H. G. Sutherland, C. L. Albury, and L. R. Griffiths, “Advances in genetics of migraine,” The Journal of Headache and Pain, vol. 20, no. 1, p. 72, Jun. 2019.
C. Gasparini, H. Sutherland, and L. Griffiths, “Studies on the pathophysiology and genetic basis of migraine,” Current Genomics, vol. 14, no. 5, pp. 300–315, 2013.
I. De Boer, A. M. J. M. van den Maagdenberg, and G. M. Terwindt, “Advance in genetics of migraine,” Current Opinion in Neurology, vol. 32, no. 3, pp. 413–421, Jun. 2019.
P. J. Goadsby, P. R. Holland, M. Martins-Oliveira, J. Hoffmann, C. Schankin, and S. Akerman, “Pathophysiology of migraine: A disorder of sensory processing,” Physiological Reviews, vol. 97, no. 2, pp. 553–622, 2017.
E. J. Mulder, C. Van Baal, D. Gaist, M. Kallela, J. Kaprio, D. A. Svensson, D. R. Nyholt, N. G. Martin, A. J. MacGregor, L. F. Cherkas, D. I. Boomsma, and A. Palotie, “Genetic and environmental influences on migraine: A twin study across six countries,” Twin Research, vol. 6, no. 5, pp. 422–431, 2003.
E. Eising and A. M. J. M. van den Maagdenberg, “Migraine; Genetics,” in the Curated Reference Collection in Neuroscience and Biobehavioral Psychology. Amsterdam, Netherland: Elsevier, 2016, pp. 42–46.
Y. Ouyang, Q. Wu, J. Li, S. Sun, and S. Sun, “Sadenosylmethionine: A metabolite critical to the regulation of autophagy,” Cell Proliferation, vol. 53, no. 11, Nov. 2020, doi: 10.1111/cpr.12891.
I. H. R. Abbasi, F. Abbasi, L. Wang, M. E. Abd El Hack, A. A. Swelum, R. Hao, J. Yao, and Y. Cao, “Folate promotes S-adenosyl methionine reactions and the microbial methylation cycle and boosts ruminants production and reproduction,” AMB Express, vol. 8, no. 1, p. 65, Dec. 2018.
C. Cyril, P. Rai, N. Chandra, P. M. Gopinath, and K. Satyamoorthy, “MTHFR gene variants C677T, A1298C and association with Down syndrome: A case-control study from South India,” Indian Journal of Human Genetics, vol. 15, no. 2, pp. 60– 64, 2009.
J. Kumar, S. K. Das, P. Sharma, G. Karthikeyan, L. Ramakrishnan, and S. Sengupta, “Homocysteine levels are associated with MTHFR A1298C polymorphism in Indian population,” Journal of Human Genetics, vol. 50, no. 12, pp. 655–663, 2005.
M. Hiraoka and Y. Kagawa, “Genetic polymorphisms and folate status,” Congenital Anomalies, vol. 57, no. 5, pp. 142–149, Sep. 2017.
J. S. Graydon, K. Claudio, S. Baker, M. Kocherla, M. Ferreira, A. Roche-Lima, J. Rodríguez-Maldonado, J. Duconge, and G. Ruaño, “Ethnogeographic prevalence and implications of the 677C>T and 1298A>C MTHFR polymorphisms in US primary care populations,” Biomarkers in Medicine, vol. 13, no. 8, pp. 649–661, Jun. 2019.
T. Angeline, N. Jeyaraj, S. Granito, and G. J. Tsongalis, “Prevalence of MTHFR gene polymorphisms (C677T and A1298C) among Tamilians,” Experimental and Molecular Pathology, vol. 77, no. 2, pp. 85–88, 2004.
N. M. J. van der Put, F. Gabreëls, E. M. B. Stevens, J. A. M. Smeitink, F. J. M. Trijbels, T. K. A. B. Eskes, L. P. van den Heuvel, and H. J. Blom, “A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects?,” The American Journal of Human Genetics, vol. 62, no. 5, pp. 1044–1051, May 1998.
R. M. Aly, M. M. Taalab, and H. F. Ghazy, “MTHFR A1298C and C677T gene polymorphisms and susceptibility to chronic myeloid leukemia in Egypt,” International journal of clinical and experimental pathology, vol. 7, no. 5, pp. 2571– 2578, 2014.
S. Fan, B. Yang, X. Zhi, Y. Wang, Q. Zheng, and G. Sun, “Combined genotype and haplotype distributions of MTHFR C677T and A1298C polymorphisms: A cross-sectional descriptive study of 13,473 Chinese adult women,” Medicine (United States), vol. 95, no. 48, p. e5355, Dec. 2016.
D. Pu, S.-W. Jiang, and J. Wu, “Association between MTHFR gene polymorphism and the risk of ovarian cancer: A meta-analysis of the literature,” Current Pharmaceutical Design, vol. 20, no. 11, pp. 1632–1638, 2014.
V. Rai, “Association of C677T polymorphism (rs1801133) in MTHFR gene with depression,” Cellular and Molecular Biology, vol. 63, no. 6, pp. 60–67, 2017.
R. Clarke, D. A. Bennett, S. Parish, P. Verhoef, M. Dötsch-Klerk, M. Lathrop, P. Xu, B. G. Nordestgaard, H. Holm, J. C. Hopewell, D. Saleheen, T. Tanaka, S. S. Anand, J. C. Chambers, M. E. Kleber, W. H. Ouwehand, Y. Yamada, C. Elbers, B. Peters, A. F. R. Stewart, M. M. Reilly, B. Thorand, S. Yusuf, J. C. Engert, T. L. Assimes, J. Kooner, J. Danesh, H. Watkins, N. J. Samani, R. Collins, and R. Peto, “Homocysteine and coronary heart disease: Meta-analysis of MTHFR case-control studies, avoiding publication bias,” PLoS Medicine, vol. 9, no. 2, p. e1001177, 2012.
S. Sitaraman, K. T. Babu, A. Badarinath, A. Pazhanimuthu, and R. Saraswathy, “Assessment of DNA damage using cytokinesis-block micronucleus cytome assay in lymphocytes of dilated cardiomyopathy patients,” Genetics Research, vol. 96, p. e001, Feb. 2014.
J. L. Brandes, “The influence of estrogen on migraine: A systematic review,” Journal of the American Medical Association, vol. 295, no. 15, pp. 1824–1830, Apr. 2006.
J. P. Herman, J. M. McKlveen, S. Ghosal, B. Kopp, A. Wulsin, R. Makinson, J. Scheimann, and B. Myers, “Regulation of the hypothalamicpituitary- adrenocortical stress response,” in Comprehensive Physiology. New Jersey: John Wiley & Sons, Inc., 2016, pp. 603–621.
V. Pizza, “Migraine and genetic polymorphisms: An overview,” The Open Neurology Journal, vol. 6, no. 1, pp. 65–70, Aug. 2012.
M. E. Bigal, T. Kurth, H. Hu, N. Santanello, and R. B. Lipton, “Migraine and cardiovascular disease: Possible mechanisms of interaction,” Neurology, vol. 72, no. 21, pp. 1864–1871, May 2009.
L. Wan, Y. Li, Z. Zhang, Z. Sun, Y. He, and R. Li, “Methylenetetrahydrofolate reductase and psychiatric diseases,” Translational Psychiatry, vol. 8, no. 1, p. 242, Dec. 2018.
S. Stuart, H. C. Cox, R. A. Lea, and L. R. Griffiths, “The role of the MTHFR gene in migraine,” Headache, vol. 52, no. 3, pp. 515–520, Mar. 2012.
M. McFall-Ngai, M. G. Hadfield, T. C. G. Bosch, H. V. Carey, T. Domazet-Lošo, A. E. Douglas, N. Dubilier, G. Eberl, T. Fukami, S. F. Gilbert, U. Hentschel, N. King, S. Kjelleberg, A. H. Knoll, N. Kremer, S. K. Mazmanian, J. L. Metcalf, K. Nealson, N. E. Pierce, J. F. Rawls, A. Reid, E. G. Ruby, M. Rumpho, J. G. Sanders, D. Tautz, and J. J. Wernegreen, “Animals in a bacterial world, a new imperative for the life sciences,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 9, pp. 3229–3236, Feb. 2013.
W. Limtrakarn, N. Tangmanee, and S. Muengtaweepongsa, “Mirror therapy rehabilitation for lower limb of acute stroke patients,” Applied Science and Engineering Progress, May 2021, doi: 10.14416/j.asep.2021.05.001.
M. V. Golja, A. Šmid, N. K. Kuželički, J. Trontelj, K. Geršak, and I. Mlinarič-Raščan, “Folate insufficiency due to MTHFR deficiency is bypassed by 5-methyltetrahydrofolate,” Journal of Clinical Medicine, vol. 9, no. 9, p. 2836, Sep. 2020.
J. Stephenson, E. Nutma, P. van der Valk, and S. Amor, “Inflammation in CNS neurodegenerative diseases,” Immunology, vol. 154, no. 2, pp. 204– 219, 2018.
S. Menon, B. Nasir, N. Avgan, S. Ghassabian, C. Oliver, R. Lea, M. Smith, and L. Griffiths, “The effect of 1 mg folic acid supplementation on clinical outcomes in female migraine with aura patients,” Journal of Headache and Pain, vol. 17, no. 1, p. 60, Dec. 2016.
Z. T. Kincses, D. Veréb, P. Faragó, E. Tóth, K. Kocsis, B. Kincses, A. Király, B. Bozsik, Á. Párdutz, D. Szok, J. Tajti, L. Vécsei, B. Tuka, and N. Szabó, “Are migraine with and without aura really different entities?,” Frontiers in Neurology, vol. 10, p. 982, Oct. 2019.
L. Liu, Y. Yu, J. He, L. Guo, H. Li, and J. Teng, “Effects of MTHFR C677T and A1298C polymorphisms on migraine susceptibility: A meta‐analysis of 26 studies,” Headache, vol. 59, no. 6, pp. 891–905, Jun. 2019.
Y. F. Lu, D. B. Goldstein, M. Angrist, and G. Cavalleri, “Personalized medicine and human genetic diversity,” Cold Spring Harbor Perspectives in Medicine, vol. 4, no. 9, pp. a008581–a008581, Sep. 2014.
I. O. Oliveira, L. P. Silva, M. C. Borges, O. M. Cruz, J. W. Tessmann, J. V. S. Motta, F. K. Seixas, B. L. Horta, and D. P. Gigante, “Interactions between lifestyle and MTHFR polymorphisms on homocysteine concentrations in young adults belonging to the 1982 Pelotas Birth Cohort,” European Journal of Clinical Nutrition, vol. 71, no. 2, pp. 259–266, Feb. 2017.
H. Nefic, M. Mackic-Djurovic, and I. Eminovic, “The Frequency of the 677C>T and 1298A>C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene in the population,” Medical Archives (Sarajevo, Bosnia and Herzegovina), vol. 72, no. 3, pp. 164–169, 2018.