Riboflavin, MTHFR genotype and blood pressure: A personalized approach to prevention and treatment of hypertension

Molecular Aspects of Medicine

Volumn 53, Issue , 2017, Pages 2-9

  McNulty, Helene ^a   Strain, J J ^a   Hughes, Catherine F ^a   Ward, Mary ^a  

^a UNIVERSITY OF ULSTER   (United Kingdom)

Author keywords

Blood pressure; Hypertension; Hypertension in pregnancy; Methylenetetrahydrofolate reductase (MTHFR) genotype; Personalized medicine; Riboflavin

Indexed keywords

5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2); RIBOFLAVIN; METHYLENETETRAHYDROFOLATE REDUCTASE (NADPH2);

BLOOD PRESSURE; CARBON METABOLISM; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; GENE LOCUS; GENETIC POLYMORPHISM; GENOME-WIDE ASSOCIATION STUDY; GENOTYPE; GENOTYPE ENVIRONMENT INTERACTION; GEOGRAPHIC DISTRIBUTION; HOMOZYGOSITY; HUMAN; HYPERTENSION; MATERNAL HYPERTENSION; MOLECULAR INTERACTION; MTHFR GENE; PERSONALIZED MEDICINE; PHENOTYPE; PUBLIC HEALTH SERVICE; REVIEW; SYSTOLIC BLOOD PRESSURE; GENETICS; PATHOPHYSIOLOGY;

BLOOD PRESSURE; GENOTYPE; HUMANS; HYPERTENSION; METHYLENETETRAHYDROFOLATE REDUCTASE (NADPH2); PRECISION MEDICINE; RIBOFLAVIN;

EID: 85006004162     PISSN: 00982997     EISSN: 18729452     Source Type: Journal    
DOI: 10.1016/j.mam.2016.10.002     Document Type: Review

References (72)

1. Academy of Medical Sciences, Stratified, personalised or P4 medicine: a new direction for placing the patient at the centre of healthcare and health education. https://www.acmedsci.ac.uk/viewFile/564091e072d41.pdf, 2015 accessed 06.06.16.
2. Also-Rallo, E., Lopez-Quesada, E., Urreizti, R., Vilaseca, A.M., Lailla, J.M., Balcells, S., et al. Polymorphisms of genes involved in homocysteine metabolism in preeclampsia and in uncomplicated pregnancies. Eur. J. Obstet. Gynecol. Reprod. Biol 120 (2005), 45–52.
3. Antoniades, C., Shirodaria, C., Warrick, N., Cai, S., de Bono, J., Lee, J., et al. 5-Methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and eNOS coupling. Circulation 114 (2006), 1193–1201.
4. Antoniades, C., Shirodaria, C., Leeson, P., Baarholm, O.A., Van-Assche, T., Cunnington, C., et al. MTHFR 677 C>T Polymorphism reveals functional importance for 5-methyltetrahydrofolate, not homocysteine, in regulation of vascular redox state and endothelial function in human atherosclerosis. Circulation 119 (2009), 2507–2515.
5. Appel, L.J., Moore, T.J., Obarzanek, E., Vollmer, W.M., Svetkey, L.P., Sacks, F.M., et al. A clinical trial of the effects of dietary patterns on blood pressure DASH Collaborative Research Group. New Engl. J. Med 336 (1997), 1117–1124.
6. Appel, L.J., Champagne, C.M., Harsha, D.W., Cooper, L.S., Obarzanek, E., Elmer, P.J., et al. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. JAMA 289 (2003), 2083–2093.
7. Bagley, P.J., Selhub, J., A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc. Nat. Acad. Sci 95 (1998), 13217–13220.
8. Bailey, L.B., Stover, P.J., McNulty, H., Fenech, M.F., Gregory, J.F. III, Mills, J.L., et al. Biomarkers of nutrition for development – folate review. J. Nutr 145 (2015), 1636S–1680S.
9. Bonter, K., Desjardins, C., Currier, N., Pun, J., Ashbur, F.D., Personalised medicine in Canada: a survey of adoption and practice in oncology, cardiology and family practice. BMJ Open 1 (2011), 1–e000110.
10. Casas, J.P., Bautista, L.E., Smeeth, L., Sharma, P., Hingorani, A.D., Homocysteine and stroke: evidence on a causal link from Mendelian randomisation. Lancet 365 (2005), 224–232.
11. Clarke, R., Bennett, D.A., Parish, S., Verhoef, P., Dotsch-Klerk, M., Lathrop, M., et al. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med, 9, 2012 e1001177.
12. Crabtree, M.J., Channon, K.M., Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease. Nitric Oxide 25 (2011), 81–88.
13. Crabtree, M.J., Tatham, A.L., Al-Wakeel, Y., Warrick, N., Hale, A.B., Cai, S., et al. Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: insights from cells with tetregulated GTP cyclohydrolase I expression. J. Biol. Chem 284 (2009), 1136–1144.
14. Ehret, G.B., Munroe, P.B., Rice, K.M., Bochud, M., Johnson, A.D., Chasman, D.I., et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478:7367 (2011), 103–109.
15. Falaschetti, E., Mindell, J., Knott, C., Poulter, N., Hypertension management in England: a serial cross-sectional study from 1994 to 2011. Lancet 9932 (2014), 1912–1919.
16. Fallaize, R., Macready, A.L., Butler, L.T., Ellis, J.A., Lovegrove, J.A., An insight into the public acceptance of nutrigenomic-based personalised nutrition. Nutr. Res. Rev 26:1 (2013), 39–48.
17. Flister, M.J., Tsaih, S.-W., O'Meara, C.C., Endres, B., Hoffman, M.J., Geurts, A.M., et al. Identifying multiple causative genes at a single GWAS locus. Genome Res 23 (2013), 1996–2002.
18. Frosst, P., Blom, H.J., Milos, R., Goyette, P., Sheppard, C.A., Matthews, R.G., et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat. Genet 10 (1995), 111–113.
19. Gaziano, T.A., Bitton, A., Anand, S., Weinstein, M.C., International Society of Hypertension. The global cost of nonoptimal blood pressure. J. Hypertens 27 (2009), 1472–1477.
20. Gibney, M., Walsh, M., The future direction of personalised nutrition: my diet, my phenotype, my genes. Proc. Nutr. Soc 72:2 (2013), 219–225.
21. Guenther, B.D., Sheppard, C.A., Tran, P., Rozen, R., Matthews, R.G., Ludwig, M.L., The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat. Struct. Biol 6 (1999), 359–365.
22. Hamburg, M.A., Collins, F.S., The path to personalized medicine. NEJM 363:4 (2010), 301–304.
23. Holmes, M.V., Newcombe, P., Hubacek, J.A., Sofat, R., Ricketts, S.L., Cooper, J., et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet 378 (2011), 584–594.
24. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke. JAMA 288 (2002), 2015–2022.
25. Horigan, G., McNulty, H., Ward, M., Strain, J.J., Purvis, J., Scott, J.M., Riboflavin lowers blood pressure in cardiovascular disease patients homozygous for the 677C>T polymorphism in MTHFR. J Hypertens 28 (2010), 478–486.
26. Hustad, S., Midttun, O., Schneede, J., Vollset, S.E., Grotmol, T., Ueland, P.M., The methylenetetrahydrofolate reductase 677C→T polymorphism as a modulator of a B vitamin network with major effects on homocysteine metabolism. Am. J. Hum. Genet 80 (2007), 846–855.
27. Jacques, P.F., Bostom, A.G., Williams, R.R., Ellison, R.C., Eckfeldt, J.H., Rosenberg, I.H., et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93 (1996), 7–9.
28. Klerk, M., Verhoef, P., Clarke, R., Blom, H.J., Kok, F.J., Schouten, E.G., et al. MTHFR C677T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 288 (2002), 2023–2031.
29. Landmesser, U., Dikalov, S., Price, S.R., McCann, L., Fukai, T., Holland, S.M., et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J. Clin. Invest 111 (2003), 1201–1209.
30. Lee, M., Hong, K.S., Chang, S.C., Saver, J.L., Efficacy of homocysteine-lowering therapy with folic acid in stroke prevention: a meta-analysis. Stroke 41 (2010), 1205–1212.
31. Levy, D., Ehret, G.B., Rice, K., Verwoert, G.C., Launer, L.J., Dehghan, A., et al. Genome-wide association study of blood pressure and hypertension. Nat. Genet 41 (2009), 677–687.
32. Lewington, S., Clarke, R., Qizilbash, N., Peto, R., Collins, R., Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360 (2002), 1903–1913.
33. Lewis, S.J., Ebrahim, S., Davey-Smith, G., Meta-analysis of the MTHFR 677C→T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventative potential of folate. Br. Med. J. 331 (2005), 1053–1059.
34. Lim, S.S., Vos, T., Flaxman, A.D., Danaei, G., Shibuya, K., Adair-Rohani, H., et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:9859 (2012), 2224–2260 Erratum, Lancet 2013, 381, 628, 1276.
35. Mainous, A.G., Johnson, S.P., Chirina, S., Baker, R., Academic family physicians’ perception of genetic testing and integration into practice: a CERA study. Fam. Med 45:4 (2013), 257–262.
36. McAuley, E., McNulty, H., Hughes, C., Strain, J.J., Ward, M., Riboflavin status, MTHFR genotype and blood pressure: current evidence and implications for personalised nutrition. Proc. Nutr. Soc, 2016 http://dx.doi.org/10.1017/S0029665116000197 Published online May12, 2016.
37. McBride, C.M., Koehly, L.M., Sanderson, S.C., Kaphingst, K.A., The behavioural response to personalised genetic information: will genetic risk profiles motivate individuals and families to choose more healthful behaviours?. Annu. Rev. Public Health 31 (2010), 89–103.
38. McNulty, H., McKinley, M.C., Wilson, B., McPartlin, J., Strain, J.J., Weir, D.G., et al. The impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent upon riboflavin status: implications for riboflavin requirements. Am. J. Clin. Nutr 76 (2002), 436–441.
39. McNulty, H., Dowey, L.R.C., Strain, J.J., Dunne, A., Ward, M., Molloy, A.M., et al. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C→T polymorphism. Circulation 113 (2006), 74–80.
40. McNulty, H., Strain, J.J., Pentieva, K., Ward, M., One-carbon metabolism and cardiovascular disease outcomes in older adults. Proc. Nutr. Soc 71 (2012), 213–221.
41. Molloy, A.M., Daly, S., Mills, J.L., Kirke, P.N., Whitehead, A.S., Ramsbottom, D., et al. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet 349 (1997), 1591–1593.
42. Mozaffarian, D., Benjamin, E.J., Go, A.S., Arnett, D.K., Blaha, M.J., Cushman, M., et al. Heart disease and stroke statistics – 2016 update: a report from the American Heart Association. Circulation 133 (2016), e38–e360.
43. Newton-Cheh, C., Johnson, T., Gateva, V., Global BPgen Consortium. Genome-wide association study identifies eight loci associated with blood pressure. Nat. Genet 41 (2009), 666–676.
44. Nishio, H., Lee, M.J., Fujii, M., Kario, K., Kayaba, K., Shimada, K., et al. A common mutation in methylenetetrahydrofolate reductase among the Japanese population. Jpn J. Hum. Genet 41 (1996), 247–251.
45. Niu, W.Q., You, Y.G., Qi, Y., Strong association of methylenetetrahydrofolate reductase gene C677T polymorphism with hypertension and hypertension-in-pregnancy in Chinese: a meta-analysis. J. Hum. Hypertens 26 (2012), 259–267.
46. Norrgard, K., DTC genetic testing for diabetes, breast cancer, heart disease and paternity. Nat. Educ, 1(1), 2008, 86.
47. Pejchal, R., Campbell, E., Guenther, B.D., Lennon, B.W., Matthews, R.G., Ludwig, M.L., Structural perturbations in the Ala→Val polymorphism of methylenetetrahydrofolate reductase: how binding of folates may protect against inactivation. Biochemistry 45 (2006), 4808–4818.
48. Qian, X., Lu, Z., Tan, M., Liu, H., Lu, D., A meta-analysis of association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and hypertension. Eur. J. Hum. Genet 15 (2007), 1239–1245.
49. Ronteltap, A., van Trijp, H., Berezowska, A., Goossens, J., Nutrigenomics-based personalised nutritional advice: in search of a business model?. Genes Nutr 8:2 (2013), 153–163.
50. Saposnik, G., Ray, J.G., Sheridan, P., McQueen, M., Lonn, E., Heart Outcomes Prevention Evaluation 2 Investigators. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke 40 (2009), 1365–1372.
51. Schmidt, K., Kolesnik, B., Gorren, A.C., Werner, E.R., Mayer, B., Cell type-specific recycling of tetrahydrobiopterin by dihydrofolate reductase explains differential effects of 7,8-dihydrobiopterin on endothelial nitric oxide synthase uncoupling. Biochem. Pharmacol 90 (2014), 246–253.
52. Stewart-Knox, B., Bunting, B., Gilpin, S., Parr, H.J., Pinhão, S., Strain, J.J., de Almeida, M.D., Gibney, M., Attitudes toward genetic testing and personalised nutrition in a representative sample of European consumers. Br. J. Nutr 101:7 (2009), 982–989.
53. Toole, J.F., Malinow, M.R., Chambless, L.E., Spence, J.D., Pettigrew, L.C., Howard, V.J., Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 291 (2004), 565–575.
54. Valdes, G., Quezada, F., Marchant, E., von Schultzendorff, A., Moran, S., Padilla, O., et al. Association of remote hypertension in pregnancy with coronary artery disease: a case-control study. Hypertension 53:4 (2009), 733–738.
55. Vikse, B.E., Irgens, L.M., Leivestad, T., Skjaerven, R., Iversen, B.M., PE and the risk of end-stage renal disease. N. Engl. J. Med 359:8 (2008), 800–909.
56. Wald, D.S., Law, M., Morris, J.K., Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br. Med. J. 325 (2002), 1202–1208.
57. Wang, X., Qin, X., Demirtas, H., Li, J., Mao, G., Huo, Y., et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 369 (2007), 1876–1882.
58. Wilcken, B., Bamforth, F., Li, Z., Zhu, H., Ritvanen, A., Redlund, M., et al. Geographical and ethnic variation of the 677C→T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J. Med. Genet 40 (2003), 619–625.
59. Williamson, J.D., Supiano, M.A., Applegate, W.B., Berlowitz, D.R., Campbell, R.C., Chertow, G.M., et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged 75 years: a randomized clinical trial. JAMA, 2016, 10.1001/jama.2016.7050 Published online May 19, 2016.
60. Wilson, C.P., McNulty, H., Scott, J.M., Strain, J.J., Ward, M., The MTHFR C677T polymorphism, B-vitamins and blood pressure. Proc. Nutr. Soc 69 (2010), 156–165.
61. Wilson, C.P., Ward, M., McNulty, H., Strain, J.J., Trouton, T.G., Horigan, G., et al. Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR 677TT genotype: a 4-y follow-up. Am. J. Clin. Nutr 95 (2012), 766–772.
62. Wilson, C.P., McNulty, H., Ward, M., Strain, J.J., Trouton, T.G., Hoeft, B.A., et al. Blood pressure in treated hypertensive individuals with the MTHFR 677TT genotype is responsive to intervention with riboflavin: findings of a targeted randomized trial. Hypertension 61 (2013), 1302–1308.
63. World Health Organization, A global brief on hypertension. WHO/DCO/WHD/2013.2. April 3. http://apps.who.int/iris/bitstream/10665/79059/1/WHO_DCO_WHD_2013.2_eng.pdf, 2013 accessed 06.08.16.
64. Wright, J.T.J., Williamson, J.D., Whelton, P.K., Snyder, J.K., Sink, K.M., Rocco, M.V., et al. A randomized trial of intensive versus standard blood-pressure control. N. Engl. J. Med 373 (2015), 2103–2116.
65. Wu, Y.L., Hu, C.Y., Lu, S.S., Gong, F.F., Feng, F., Qian, Z.Z., et al. Associations between methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and essential hypertension: a systematic review and meta-analysis. Metabolism 63 (2014), 1503–1511.
66. Xia, X., Chang, W., Cao, Y., Meta-analysis of the methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to preeclampsia. Hypertens. Res 35 (2012), 1129–1134.
67. Xie, X., Atkins, E., Lv, J., Bennett, A., Neal, B., Ninomiya, T., et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet 387 (2016), 435–443.
68. Yamada, K., Chen, Z., Rozen, R., Matthews, R.G., Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proc. Natl. Acad. Sci. U.S.A. 98 (2001), 14853–14858.
69. Yang, B., Fan, S., Zhi, X., Li, Y., Liu, Y., Wang, D., et al. Associations of MTHFR gene polymorphisms with hypertension and hypertension in pregnancy: a meta-analysis from 114 studies with 15411 cases and 21970 controls. PLoS ONE, 9, 2014 e87497.
70. Yang, K.M., Jia, J., Mao, L., Men, C., Tang, K.T., Li, Y.Y., et al. Methylenetetrahydrofolate reductase C677T gene polymorphism and essential hypertension: a meta-analysis of 10,415 subjects. Biomed. Rep 2 (2014), 699–708.
71. Yang, Q., Botto, L.D., Erickson, J.D., Berry, R.J., Sambell, C., Johansen, H., et al. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation 113 (2006), 1335–1343.
72. Yusuf, S., Hawken, S., Ounpuu, S., Dans, T., Avezum, A., Lana, F., et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364 (2004), 937–952.