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Effects of methionine synthase and methionine synthase reductase polymorphisms on hypertension susceptibility

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Abstract

Background

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene are strongly associated with hypertension incidence, although such association is inconsistent among ethnicities studied. However, effects of polymorphisms of other genes related to folate metabolism besides MTHFR on hypertension susceptibility are not well known yet.

Objective

The aim of this study was to elucidate whether methionine synthase (MTR) 2756A>G and methionine synthase reductase (MTRR) 66A>G polymorphisms might be associated with risks of hypertension susceptibility in the Korean population.

Methods

Genotyping of these two polymorphisms was performed for 232 hypertensive patients and 247 unrelated healthy controls using polymerase chain reaction-restriction fragment length polymorphism technique.

Results

In the present study, mutations of MTR 2756A>G and MTRR 66A>G polymorphisms were associated with increased and decreased susceptibility to hypertension, respectively. Allele combinations from these two polymorphisms were also related to hypertension prevalence. When polymorphism data were stratified according to clinical components of hypertension, The G allele of MTR 2756A>G polymorphism was significantly associated with an increased risk of hypertension in subjects with BMI < 26.1 kg/m2 (P = 0.004), WC < 87.2 in. (P = 0.021), FBG < 95.5 mg/dL (P = 0.011), triglyceride < 133.5 mg/dL (P = 0.034), and HDL-cholesterol < 52.2 mg/dL (P = 0.036). The G allele of MTRR 66A>G polymorphism was significantly associated with a decreased risk of hypertension in subjects with WC ≥ 87.2 in. (P = 0.029), FBG ≥ 95.5 mg/dL (P = 0.032) and triglyceride ≥ 133.5 mg/dL (P = 0.027).

Conclusion

MTR 2756A>G and MTRR 66A>G polymorphisms related to folate metabolism might be genetic markers for risk of hypertension in the Korean population.

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References

  • Anwar W, Gueant JL, Abdelmouttaleb I, Adjalla C, Gerard P, Lemoel G, Erraess N, Moutabarrek A, Namour F (2001) Hyperhomocysteinemia is related to residual glomerular filtration and folate, but not to methylenetetrahydrofolate-reductase and methionine synthase polymorphisms, in supplemented end-stage renal disease patients undergoing hemodialysis. Clin Chem Lab Med 39:747–752

    Article  CAS  Google Scholar 

  • Boushey CJ, Beresford SA, Omenn GS, Motulsky AG (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 274:1049–1057

    Article  CAS  Google Scholar 

  • Brattstrom L, Wilcken DE (2000) Homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr 72:315–323

    Article  CAS  Google Scholar 

  • Chen J, Stampfer MJ, Ma J, Selhub J, Malinow MR, Hennekens CH, Hunter DJ (2001) Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction. Atherosclerosis 154:667–672

    Article  CAS  Google Scholar 

  • Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I (1991) Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 324:1149–1155

    Article  CAS  Google Scholar 

  • Dekou V, Gudnason V, Hawe E, Miller GJ, Stansbie D, Humphries SE (2001) Gene-environment and gene–gene interaction in the determination of plasma homocysteine levels in healthy middle-aged men. Thromb Haemost 85:67–74

    Article  CAS  Google Scholar 

  • Du B, Tian H, Tian D, Zhang C, Wang W, Wang L, Ge M, Hou Q, Zhang W (2018) Genetic polymorphisms of key enzymes in folate metabolism affect the efficacy of folate therapy in patients with hyperhomocysteinaemia. Br J Nutr 119:887–895

    Article  CAS  Google Scholar 

  • Fowdar JY, Lason MV, Szvtko AL, Lea RA, Griffiths LR (2012) Investigation of homocysteine-pathway-related variants in essential hypertension. Int J Hypertens 2012:190923

    Article  Google Scholar 

  • Fowler B (2001) The folate cycle and disease in humans. Kidney Int Suppl 78:S221–229

    Article  CAS  Google Scholar 

  • Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113

    Article  CAS  Google Scholar 

  • Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 7:195–200

    Article  CAS  Google Scholar 

  • Harmon DL, Shields DC, Woodside JV, McMaster D, Yarnell JW, Young IS, Peng K, Shane B, Evans AE, Whitehead AS (1999) Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations. Genet Epidemiol 17:298–309

    Article  CAS  Google Scholar 

  • Huang L, Song XM, Zhu WL, Li Y (2008) Plasma homocysteine and gene polymorphisms associated with the risk of hyperlipidemia in northern Chinese subjects. Biomed Environ Sci 21:514–520

    Article  CAS  Google Scholar 

  • Hyndman ME, Bridge PJ, Warnica JW, Fick G, Parsons HG (2000) Effect of heterozygosity for the methionine synthase 2756 A%3eG mutation on the risk for recurrent cardiovascular events. Am J Cardiol 86:1144–1146

    Article  CAS  Google Scholar 

  • Jemaa R, Achouri A, Kallel A, Ben Ali S, Mourali S, Feki M, Elasmi M, Raieb SH, Sanhaji H, Omar S et al (2756A) Association between the 2756A%3e G variant in the gene encoding methionine synthase and myocardial infarction in Tunisian patients. Clin Chem Lab Med 46:1364–1368

    Article  CAS  Google Scholar 

  • Jiang S, Zhao R, Pan M, Venners SA, Zhong G, Hsu YH (2014) Associations of MTHFR and MTRR polymorphisms with serum lipid levels in Chinese hypertensive patients. Clin Appl Thromb Hemost 20:400–410

    Article  Google Scholar 

  • Kahleová R, Palyzová D, Zvára K, Zvárová J, Hrach K, Nováková I, Hyánek J, Bendlová B, Kozich V (2002) Essential hypertension in adolescents: association with insulin resistance and with metabolism of homocysteine and vitamins. Am J Hypertens 15:857–864

    Article  Google Scholar 

  • Kim YR, Kim SH, Kang SH, Kim HJ, Kong MH, Hong S-H (2014) Association of the K173R variant and haplotypes in the aldosterone synthase gene with essential hypertension. Genes Genom 36:625–632

    Article  CAS  Google Scholar 

  • Klerk M, Lievers KJ, Kluijtmans LA, Blom HJ, den Jeijer M, Schouten EG, Kok FJ, Verhoef P (2756A) The 2756A%3eG variant in the gene encoding methionine synthase: its relation with plasma homocysteine levels and risk of coronary heart disease in a Dutch case–control study. Throm Res 110:87–91

    Article  CAS  Google Scholar 

  • Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M, Eydoux P, Rosenblatt DS, Rozen R, Gravel RA (1996) Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Hum Mol Genet 5:1867–1874

    Article  CAS  Google Scholar 

  • Leclerc D, Wilson A, Dumas R, Gafuik C, Song D, Watkins D, Heng HH, Rommens JM, Scherer SW, Rosenblatt DS et al (1998) Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria. Proc Natl Acad Sci USA 95:3059–3064

    Article  CAS  Google Scholar 

  • Li WX, Lv WW, Dai SX, Pan ML, Huang JF (2015a) Joint associations of folate, homocysteine and MTHFR, MTR and MTRR gene polymorphisms with dyslipidemia in a Chinese hypertensive population: a cross-sectional study. Lipid Health Dis 14:101

    Article  Google Scholar 

  • Li WX, Dai SX, Zheng JJ, Liu JQ, Huang JF (2015b) Homocysteine metabolism gene polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) jointly elevate the risk of folate deficiency. Nutrients 7:6670–6687

    Article  CAS  Google Scholar 

  • Li WX, Liao P, Hu CY, Cheng F, Zhang T, Sun YY, Tang L, Wang MM, Liu KS, Liu D (2017) Interactions of methylenetetrahydrofolate reductase gene polymorphisms, folate, and homocysteine on blood pressure in a Chinese hypertensive population. Clin Lab 63:817–825

    CAS  PubMed  Google Scholar 

  • Linnebank M, Fliessbach K, Kolsch H, Rietschel M, Wullner U (2005) The methionine synthase polymorphism c.2756Aright curved arrow G (D919G) is relevant for disease-free longevity. Int J Mol Med 16:759–761

    CAS  PubMed  Google Scholar 

  • Ma J, Stampfer MJ, Christensen B, Giovannucci E, Hunter DJ, Chen J, Willett WC, Selhub J, Hennekens CH, Gravel R, Rozen R (1999) A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Cancer Epidemiol Biomark Prev 8:825–829

    CAS  Google Scholar 

  • Moskau S, Farmand S, Semmler A, Wüllner U, Pohl C, Klockgether T, Linnebank M (2007) The methionine synthase polymorphism c.2756A%3eG (D919G) influences diastolic blood pressure. J Hum Hypertens 21:418–420

    Article  CAS  Google Scholar 

  • Nazki FH, Sameer AS, Ganaie BA (2014) Folate: metabolism, genes, polymorphisms and the associated diseases. Gene 533:11–20

    Article  CAS  Google Scholar 

  • Raina JK, Sharma M, Panjaliya RK, Bhagat M, Sharma R, Bakaya A, Kumar P (2016) Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G gene polymorphisms and associated risk of cardiovascular diseases: a study from Jammu region. Indian Heart J 68:421–430

    Article  Google Scholar 

  • Rozen R (1997) Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Throm Haemost 78:523–526

    Article  CAS  Google Scholar 

  • Scazzone C, Acuto S, Guglielmini E, Campisi G, Bono A (2009) Methionine synthase reductase (MTRR) A66G polymorphism is not related to plasma homocysteine concentration and the risk for vascular disease. Exp Mol Pathol 86:131–133

    Article  CAS  Google Scholar 

  • Sharp L, Little J (2004) Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol 159:423–443

    Article  Google Scholar 

  • Silaste ML, Rantala M, Sampi M, Alfthan G, Aro A, Kesäniemi YA (2001) Polymorphisms of key enzymes in homocysteine metabolism affect diet responsiveness of plasma homocysteine in healthy women. J Nutr 131:2643–2647

    Article  CAS  Google Scholar 

  • van der Put NM, van der Molen EF, Kluijtmans LA, Heil SG, Trijbels JM, Eskes TK, Van Oppenraaij-Emmerzaal D, Banerjee R, Blom HJ (1997) Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease. QJM 90:511–517

    Article  Google Scholar 

  • Vaughn JD, Bailey LB, Shelnutt KP, Dunwoody KM, Maneval DR, Davis SR, Quinlivan EP, Gregory JF, Kauwell GP (2004) Methionine synthase reductase 66A→G polymorphism is associated with increased plasma homocysteine concentration when combined with the homozygous methylenetetrahydrofolate reductase 677C→T variant. J Nutr 134:2985–2990

    Article  CAS  Google Scholar 

  • Vinukonda G, Shaik Mohammad N, Md Nurul Jain J, Prasad Chintakindi K, Rama Devi Akella R (2009) Genetic and environmental influences on total plasma homocysteine and coronary artery disease (CAD) risk among South Indians. Clin Chim Acta 405:127–131

    Article  CAS  Google Scholar 

  • Wang J, Ouyang N, Qu L, Lin T, Zhang X, Yu Y, Jiang C, Xie L, Wang L, Wang Z et al (2017) Effect of MTHFR A1298C and MTRR A66G genetic mutations on homocysteine levels in the Chinese population: a systematic review and meta-analysis. J Trans Int Med 5:220–222

    Article  Google Scholar 

  • Wilson A, Platt R, Wu Q, Leclerc D, Christensen B, Yang H, Gravel RA, Rozen R (1999) A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab 67:317–323

    Article  CAS  Google Scholar 

  • Yi P, Melnyk K, Pogribna M, Pogribny IP, Hine RJ, James SJ (2000) Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J Biol Chem 38:29318–29323

    Article  Google Scholar 

  • Zhang Y, Zhang M, Niu T, Xu X, Zhu G, Huo Y, Chen C, Wang X, Xing H, Peng S (2004) D919G polymorphism of methionine synthase gene is associated with blood pressure response to benazepril in Chinese hypertensive patients. J Hum Genet 49:296–301

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by a research Grant from Jeju National University Hospital development fund in 2016.

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Authors and Affiliations

  1. Department of Laboratory Medicine, School of Medicine, Jeju National University, Jeju, 63243, Republic of Korea

    Young Ree Kim & Sung Ha Kang

  2. Department of Science Education, Teachers College, Jeju National University, Jeju, 63294, Republic of Korea

    Seung-Ho Hong

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  1. Young Ree Kim
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Correspondence to Seung-Ho Hong.

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Young Ree Kim, Sung Ha Kang and Seung-Ho Hong declare that there is no conflict of interests or financial interests on this article contents.

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Written informed consent was approved by the Institutional Review Board of Jeju National University Hospital. The experimental procedures followed the standard regulation of the Review Board.

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Kim, Y.R., Kang, S.H. & Hong, SH. Effects of methionine synthase and methionine synthase reductase polymorphisms on hypertension susceptibility. Genes Genom 42, 477–483 (2020). https://doi.org/10.1007/s13258-020-00917-9

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