RELATIONSHIP OF POLYMORPHISM RS1801133 OF THE MTHFR GENE WITH THE DEVELOPMENT OF H-TYPE HYPERTENSION DISEASE
DOI:
https://doi.org/10.11603/1811-2471.2023.v.i2.13788Keywords:
hypertension, homocysteine, gene, MTHFR, polymorphism, C677TAbstract
SUMMARY. Cardiovascular diseases are still in the first place among the causes of mortality in Ukraine and other countries. According to the WHO, there is a progressive increase in cases of hypertension in the world. One of the forms resistant to treatment according to standard protocols of antihypertensive drugs is the H-type of essential hypertension, which is associated with hyperhomocysteinemia. Today, the study of genetic factors for the occurrence of GC is relevant for the possibility of developing targeted therapy, as well as adjusting treatment protocols for hyperhomocysteinemia associated with hypertension.
The aim – to analyze the presence and nature of the connection between the C677T polymorphism of the MTHFR gene with the level of blood pressure and hyperhomocysteinemia, to study the main links of the pathogenesis of H-type hypertension; to analyze the pathogenesis of the development of H-HTN.
Material and Methods. 27 subjects took part in the study, who had homocysteine levels determined, and a general clinical examination was performed. 17 of them were diagnosed with H-type hypertension. They made up the main (I) group. The control (II) group consisted of 10 people without cardiovascular and other pathologies and with normal levels of homocysteine. All examinees underwent a genetic study of C677T of the MTHFR gene by PCR.
Results. In the main (I) group, a high prevalence of the homozygous state for the mutant T allele (70.6 %) was noted, which correlated with an increase in the degree of GC and the level of hyperhomocysteinemia. 17.6 % of patients with the TT genotype had 2nd-degree hypertension, and 52.9 % had 3rd-degree severity. Homocysteine levels were significantly higher than normal and were associated with resistance to standard treatment protocols.
Conclusions. H-type GC is associated with the presence of a mutation in the MTHFR gene, the TT genotype of which is correlated with an increased blood pressure level and leads to an increase in the severity of arterial hypertension. Therefore, the detection of the C677T polymorphism will allow for predicting the development of resistant GC and adjusting the therapeutic tactics in the treatment of such patients.
References
NCD Risk Factor Collaboration (NCD-RisC) (2021). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet (London, England), 398 (10304), 957–980. https://doi.org/10.1016/S0140-6736(21)01330-1
NCD Risk Factor Collaboration (NCD-RisC) (2017). Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19·1 million participants. Lancet (London, England), 389(10064), 37–55. https://doi.org/10.1016/S0140-6736(16)31919-5
Zhou, B., Perel, P., Mensah, G. A., & Ezzati, M. (2021). Global epidemiology, health burden and effective interventions for elevated blood pressure and hypertension. Nature reviews. Cardiology, 18(11), 785–802. https://doi.org/10.1038/s41569-021-00559-8
Unger, T., Borghi, C., Charchar, F., Khan, N. A., Poulter, N. R., Prabhakaran, D., Ramirez, A., Schlaich, M., Stergiou, G. S., Tomaszewski, M., Wainford, R. D., Williams, B., & Schutte, A. E. (2020). 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension (Dallas, Tex. : 1979), 75(6), 1334–1357. https://doi.org/10.1161/HYPERTENSIONAHA.120.15026
Koval, S., Snigurska, I., Bozhko, V., & Miloslavsky, D. (2021). The problem of hypertensive heart disease regression in patients with arterial hypertension. HYPERTENSION, 13(6), 28–34. https://doi.org/10.22141/2224-1485.13.6.2020.223078
World Health Organization (WHO) Raised Blood Pressure. 2019. [(accessed on 25 August 2021)]. Available online: https://www.who.int/news-room/fact-sheets/detail/hypertension
Sadeghian, S., Fallahi, F., Salarifar, M., Davoodi, G., Mahmoodian, M., Fallah, N., Darvish, S., Karimi, A., & Tehran Heart Center (2006). Homocysteine, vitamin B12 and folate levels in premature coronary artery disease. BMC cardiovascular disorders, 6, 38. https://doi.org/10.1186/1471-2261-6-38
Guo, H., Chi, J., Xing, Y., & Wang, P. (2009). Influence of folic acid on plasma homocysteine levels & arterial endothelial function in patients with unstable angina. The Indian journal of medical research, 129(3), 279–284.
Hankey, G. J., & Eikelboom, J. W. (1999). Homocysteine and vascular disease. Lancet (London, England), 354(9176), 407–413. https://doi.org/10.1016/S0140-6736(98)11058-9
Wang, W., Ji, P., Wang, Y., Guo, H., Bian, R., Xu, J., & Xiong, Y. (2018). Prevalence of hyperhomocysteinemia and its associated factors in patients with primary hypertension in Chinese urban communities: A cross-sectional study from Nanjing. Clinical and experimental hypertension (New York, N.Y. : 1993), 40(5), 495–500. https://doi.org/10.1080/10641963.2017.1403621
Lim, U., & Cassano, P. A. (2002). Homocysteine and blood pressure in the Third National Health and Nutrition Examination Survey, 1988-1994. American journal of epidemiology, 156(12), 1105–1113. https://doi.org/10.1093/aje/kwf157
Li, S., Li, G., Luo, X., Huang, Y., Wen, L., & Li, J. (2021). Endothelial Dysfunction and Hyperhomocysteinemia-Linked Cerebral Small Vessel Disease: Underlying Mechanisms and Treatment Timing. Frontiers in neurology, 12, 736309. https://doi.org/10.3389/fneur.2021.736309
Liu, L. S., & Writing Group of 2010 Chinese Guidelines for the Management of Hypertension (2011). Zhonghua xin xue guan bing za zhi, 39(7), 579–615.
Flister, M. J., Tsaih, S. W., O'Meara, C. C., Endres, B., Hoffman, M. J., Geurts, A. M., Dwinell, M. R., Lazar, J., Jacob, H. J., & Moreno, C. (2013). Identifying multiple causative genes at a single GWAS locus. Genome research, 23(12), 1996–2002. https://doi.org/10.1101/gr.160283.113
https://www.genecards.org/cgi-bin/carddisp.pl?gene=MTHFR
Nursal, A. F., Kaya, S., Sezer, O., Karakus, N., & Yigit, S. (2018). MTHFR gene C677T and A1298C variants are associated with FMF risk in a Turkish cohort. Journal of clinical laboratory analysis, 32(2), e22259. https://doi.org/10.1002/jcla.22259
Ren, Y., He, Y. H., & Cao, M. J. (2018). Correlation analysis of MTHFR andMTRR gene related mutations with H type hypertension. J. Yan’an U, 16(3), 73-76
Pereira, A. C., Schettert, I. T., Morandini Filho, A. A., Guerra-Shinohara, E. M., & Krieger, J. E. (2004). Methylenetetrahydrofolate reductase (MTHFR) c677t gene variant modulates the homocysteine folate correlation in a mild folate-deficient population. Clinica chimica acta; international journal of clinical chemistry, 340(1-2), 99–105. https://doi.org/10.1016/j.cccn.2003.09.016
Goyette, P., Sumner, J. S., Milos, R., Duncan, A. M., Rosenblatt, D. S., Matthews, R. G., & Rozen, R. (1994). Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nature genetics, 7(2), 195–200. https://doi.org/10.1038/ng0694-195
Li, J., Jiang, S., Zhang, Y., Tang, G., Wang, Y., Mao, G., Li, Z., Xu, X., Wang, B., & Huo, Y. (2015). H-type hypertension and risk of stroke in chinese adults: A prospective, nested case-control study. Journal of translational internal medicine, 3(4), 171–178. https://doi.org/10.1515/jtim-2015-0027
Smith, A. D., & Refsum, H. (2021). Homocysteine - from disease biomarker to disease prevention. Journal of internal medicine, 290(4), 826–854. https://doi.org/10.1111/joim.13279
Nakata, Y., Katsuya, T., Takami, S., Sato, N., Fu, Y., Ishikawa, K., Takiuchi, S., Rakugi, H., Miki, T., Higaki, J., & Ogihara, T. (1998). Methylenetetrahydrofolate reductase gene polymorphism: relation to blood pressure and cerebrovascular disease. American journal of hypertension, 11(8 Pt 1), 1019–1023. https://doi.org/10.1016/s0895-7061(98)00046-6
Конвенція про захист прав і гідності людини щодо застосування біології та медицини: Конвенція про права людини та біомедицину. Редакція від 25.01.2005, підстава - 994_686
Rodríguez-Esparragón, F., Hernández-Perera, O., Rodríguez-Pérez, J. C., Anábitarte, A., Díaz-Cremades, J. M., Losada, A., Fiuza, D., Hernández, E., Yunis, C., & Ferrario, C. M. (2003). The effect of methylenetetrahydrofolate reductase C677T common variant on hypertensive risk is not solely explained by increased plasma homocysteine values. Clinical and experimental hypertension (New York, N.Y. : 1993), 25(4), 209–220. https://doi.org/10.1081/ceh-120020391
Cortese, C., & Motti, C. (2001). MTHFR gene polymorphism, homocysteine and cardiovascular disease. Public health nutrition, 4(2B), 493–497. https://doi.org/10.1079/phn2001159
Meng, H., Huang, S., Yang, Y., He, X., Fei, L., & Xing, Y. (2021). Association Between MTHFR Polymorphisms and the Risk of Essential Hypertension: An Updated Meta-analysis. Frontiers in genetics, 12, 698590. https://doi.org/10.3389/fgene.2021.698590
Qian, X., Lu, Z., Tan, M., Liu, H., & Lu, D. (2007). A meta-analysis of association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and hypertension. European journal of human genetics : EJHG, 15(12), 1239–1245. https://doi.org/10.1038/sj.ejhg.5201914
Liu, H. Y., Ma, P., & Xu, Q. B. (2011). The correlation between polymorphisms of N5, 10 methylenetetrahydrofolate reductase and essential hypertension in Han population in Ningxia. Guangdong Med J, 32(15), 1977-1980.
Yang, K. M., Jia, J., Mao, L. N., Men, C., Tang, K. T., Li, Y. Y., Ding, H. X., & Zhan, Y. Y. (2014). Methylenetetrahydrofolate reductase C677T gene polymorphism and essential hypertension: A meta-analysis of 10,415 subjects. Biomedical reports, 2(5), 699–708. https://doi.org/10.3892/br.2014.302
Zhang, C., Dou, Z., Zhao, C., Li, J., Xin, Q., Feng, Y., Xie, Y., & Cao, J. (2022). Analysis of the Correlation between the Distribution of MTHFR Gene and the Severity and Renal Function of Elderly Patients with H-Type Hypertension. Journal of healthcare engineering, 2022, 8352005. https://doi.org/10.1155/2022/8352005
Ward, M., Hughes, C. F., Strain, J. J., Reilly, R., Cunningham, C., Molloy, A. M., Horigan, G., Casey, M., McCarroll, K., O'Kane, M., Gibney, M. J., Flynn, A., Walton, J., McNulty, B. A., McCann, A., Kirwan, L., Scott, J. M., & McNulty, H. (2020). Impact of the common MTHFR 677C→T polymorphism on blood pressure in adulthood and role of riboflavin in modifying the genetic risk of hypertension: evidence from the JINGO project. BMC medicine, 18(1), 318. https://doi.org/10.1186/s12916-020-01780-x
Joffres, M., Falaschetti, E., Gillespie, C., Robitaille, C., Loustalot, F., Poulter, N., McAlister, F. A., Johansen, H., Baclic, O., & Campbell, N. (2013). Hypertension prevalence, awareness, treatment and control in national surveys from England, the USA and Canada, and correlation with stroke and ischaemic heart disease mortality: a cross-sectional study. BMJ open, 3(8), e003423. https://doi.org/10.1136/bmjopen-2013-003423
Sutton-Tyrrell, K., Bostom, A., Selhub, J., & Zeigler-Johnson, C. (1997). High homocysteine levels are independently related to isolated systolic hypertension in older adults. Circulation, 96(6), 1745–1749. https://doi.org/10.1161/01.cir.96.6.1745
Sen, U., Mishra, P. K., Tyagi, N., & Tyagi, S. C. (2010). Homocysteine to hydrogen sulfide or hypertension. Cell biochemistry and biophysics, 57(2-3), 49–58. https://doi.org/10.1007/s12013-010-9079-y
Yang, G., Wu, L., Jiang, B., Yang, W., Qi, J., Cao, K., Meng, Q., Mustafa, A. K., Mu, W., Zhang, S., Snyder, S. H., & Wang, R. (2008). H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science (New York, N.Y.), 322(5901), 587–590. https://doi.org/10.1126/science.1162667
Rochette, L., & Vergely, C. (2008). Le sulfure d'hydrogène (H2S), un gaz endogène à l'odeur d'oeuf pourri, pourrait être un régulateur des fonctions cardiovasculaires [Hydrogen sulfide (H2S), an endogenous gas with odor of rotten eggs might be a cardiovascular function regulator]. Annales de cardiologie et d'angeiologie, 57(3), 136–138. https://doi.org/10.1016/j.ancard.2008.02.014
Zhao, W., Zhang, J., Lu, Y., & Wang, R. (2001). The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. The EMBO journal, 20(21), 6008–6016. https://doi.org/10.1093/emboj/20.21.6008
Spence J. D. (2001). Patients with atherosclerotic vascular disease: how low should plasma homocyst(e)ine levels go?. American journal of cardiovascular drugs : drugs, devices, and other interventions, 1(2), 85–89. https://doi.org/10.2165/00129784-200101020-00002
Ansari, E., Anderson, B., & Kauser, K. (2021). Retained Functionality of Atherosclerotic Human Arteries Following Photoactivated Linking of the Extracellular Matrix by Natural Vascular Scaffolding Treatment. Journal of cardiovascular translational research, 14(3), 441–448. https://doi.org/10.1007/s12265-020-10063-y
Kumar, M., & Sandhir, R. (2018). Neuroprotective Effect of Hydrogen Sulfide in Hyperhomocysteinemia Is Mediated Through Antioxidant Action Involving Nrf2. Neuromolecular medicine, 20(4), 475–490. https://doi.org/10.1007/s12017-018-8505-y
Distrutti, E., Mencarelli, A., Santucci, L., Renga, B., Orlandi, S., Donini, A., Shah, V., & Fiorucci, S. (2008). The methionine connection: homocysteine and hydrogen sulfide exert opposite effects on hepatic microcirculation in rats. Hepatology (Baltimore, Md.), 47(2), 659–667. https://doi.org/10.1002/hep.22037
Baszczuk, A., Kopczyński, Z., & Thielemann, A. (2014). Dysfunkcja śródbłonka naczyniowego u chorych na pierwotne nadciśnienie tętnicze z hiperhomocysteinemią [Endothelial dysfunction in patients with primary hypertension and hyperhomocysteinemia]. Postepy higieny i medycyny doswiadczalnej (Online), 68, 91–100. https://doi.org/10.5604/17322693.1087521
Chandra, A., & Angle, N. (2005). Vascular endothelial growth factor stimulates a novel calcium-signaling pathway in vascular smooth muscle cells. Surgery, 138(4), 780–787. https://doi.org/10.1016/j.surg.2005.07.010
Pan, Y., Ye, S., Yuan, D., Zhang, J., Bai, Y., & Shao, C. (2014). Hydrogen sulfide (H2S)/cystathionine γ-lyase (CSE) pathway contributes to the proliferation of hepatoma cells. Mutation research, 763-764, 10–18. https://doi.org/10.1016/j.mrfmmm.2014.03.002
Huang, X., Akgün, E. E., Mehmood, K., Zhang, H., Tang, Z., & Li, Y. (2022). Mechanism of Hypoxia-Mediated Smooth Muscle Cell Proliferation Leading to Vascular Remodeling. BioMed research international, 2022, 3959845. https://doi.org/10.1155/2022/3959845
Zhang, S., Bai, Y. Y., Luo, L. M., Xiao, W. K., Wu, H. M., & Ye, P. (2014). Association between serum homocysteine and arterial stiffness in elderly: a community-based study. Journal of geriatric cardiology : JGC, 11(1), 32–38. https://doi.org/10.3969/j.issn.1671-5411.2014.01.007
McMahon, A., McNulty, H., Hughes, C. F., Strain, J. J., & Ward, M. (2016). Novel Approaches to Investigate One-Carbon Metabolism and Related B-Vitamins in Blood Pressure. Nutrients, 8(11), 720. https://doi.org/10.3390/nu8110720
