Portal de Periódicos da CAPES

The T Allele of The C 677 T 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism May Protect Endothelial Function in Young, Normal Subjects

2002; Lippincott Williams & Wilkins; Volume: 22; Issue: 1 Linguagem: Inglês

10.1161/atvb.22.1.193

1524-4636

Rob Butler, Andrew D. Morris, Allan D. Struthers,

Moyamoya disease diagnosis and treatment

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 22, No. 1The T Allele of The C677T 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism May Protect Endothelial Function in Young, Normal Subjects Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBThe T Allele of The C677T 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism May Protect Endothelial Function in Young, Normal Subjects Rob Butler, Andrew D. Morris and Allan D. Struthers Rob ButlerRob Butler University Department of Clinical Pharmacology and Therapeutics (R.B., A.D.S),, University Department of Medicine (A.D.M.) and The Diabetes Centre (A.D.M.), Ninewells Hospital and Medical School, Dundee,, United Kingdom , Andrew D. MorrisAndrew D. Morris University Department of Clinical Pharmacology and Therapeutics (R.B., A.D.S),, University Department of Medicine (A.D.M.) and The Diabetes Centre (A.D.M.), Ninewells Hospital and Medical School, Dundee,, United Kingdom and Allan D. StruthersAllan D. Struthers University Department of Clinical Pharmacology and Therapeutics (R.B., A.D.S),, University Department of Medicine (A.D.M.) and The Diabetes Centre (A.D.M.), Ninewells Hospital and Medical School, Dundee,, United Kingdom Originally published15 Mar 2018https://doi.org/10.1161/atvb.22.1.193Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:193–194To the Editor:There is a modest amount of data suggesting hyperhomocysteinemia may be a determinant of vascular diseases such as stroke1 and myocardial infarction.2 However, this finding has not been confirmed in longitudinal studies,3 4 and this has led to the suggestion by Evans et al3 that higher homocysteine levels may be an effect of vascular disease rather than the cause of it. A recent meta-analysis suggests that the MTHFR genotype leads to mild hyperhomocysteinemia but not to vascular disease5 and may be an epiphenomena as the result of an association with other risk factors such as male sex, hypertension, smoking, hyperlipidemia, and reduced renal clearance.Hyperhomocysteinemia can result from either genetic or nutritional causes. The MTHFR gene controls the remethylation of homocysteine to methionine and has been reported to cause mild hyperhomocysteinaemia.6 Case control studies have reported an association among the MTHFR polymorphism, cardiovascular disease, and myocardial infarction.7 8 However, the association is also inconclusive as others have reported no link between the genotype and cardiovascular events.9 This gained further support when Demuth et al10 demonstrated opposite effects of hyperhomocysteinemia and the MTHFR C677T mutation, showing that homocysteine positively correlated with carotid lumen diameter and TT homozygotes negatively correlated with lumen diameter. Similarly, there was no link between the MTHFR genotype and homocysteine level in this study. One way to help clarify whether a possible culprit is a cause of vascular disease, or a result of it, is to study young men before any overt vascular disease has occurred.In this report, therefore we present a cross-sectional study of normal young men (n=68), investigating the impact of the T allele on endothelial function assessed by venous occlusion plethysmography. Our methods have been described previously.11 The C allele occurred in 62% and T allele in 38% of subjects (polymorphic ratio of 36:32 patients, CC:CT/TT, respectively). There were no differences in age or levels of homocysteine between groups. (Table 1) Table 1. Blood Flow Responses to Infused Agents and Demographic Details by GenotypeCC Genotype (Mean±SD)CT/TT Genotype (Mean±SD)P Value (95% CI)BMI indicates body mass index.Baseline blood flow, mL · 100 mL−1 · min−1 Day 13.09±1.333.27±1.960.64 Day 22.61±1.372.75±1.370.67Acetylcholine3.52±1.994.19±2.100.017 (0.13, 1.27)Nitroprusside2.36±1.232.76±1.250.028 (0.04, 0.72)Verapamil4.40±2.354.71±2.150.27 (0.31, 0.94)Monomethyl-l-arginine0.83±0.230.80±0.210.25 (0.09, 0.03)Norepinephrine0.65±0.210.64±0.170.56 (0.07, 0.04)Blood pressure, mm Hg117/74±8/7118/72±9/70.55/0.20Age, years24.0±5.225.3±6.00.33BMI, mol/L23.3±2.723.0±2.10.62Smokersn=14n=15Cholesterol, mol/L3.9±0.84.1±1.00.53HDL, Chol mol/L1.25±0.301.18±0.170.30Homocysteine8.8±3.29.5±3.70.39B12, pg/mL393.1±101.3315.9±95.00.003Folate, pg/mL6.3±3.85.3±1.70.20We found that the CC genotype was associated with a significant impairment in endothelial-dependent vasodilatation. There was also a significant difference with our control endothelial independent, NO-donating vasodilator nitroprusside, although not with verapamil which is NO independent. There were no significant differences between genotypes for either endothelial-dependent and -independent vasoconstrictors, monomethyl-l-arginine and norepinephrine, respectively. When quartiles of plasma folate were examined, the blood flow differences between genotypes rested entirely in those with the lowest quartile of plasma folate. All plasma folate levels were within the normal range. (Table 2) Table 2. Effects of Folate Quartile on Blood Flow Ratio by MTHFR GenotypeCC Genotype (Mean±SD)CT/TT Genotype (Mean±SD)P ValueL-NMMA indicates NG-monomethyl-l-arginine.1st quartile Acetylcholine2.7±1.53.8±1.40.01 Nitroprusside2.0±0.82.6±0.7<0.01 Verapamil3.5±1.34.9±2.20.01 L-NMMA0.84±0.180.77±0.160.18 Norepinephrine0.73±0.170.59±0.16<0.012nd–4th quartiles Acetylcholine3.7±2.14.3±2.30.08 Nitroprusside2.4±1.32.8±1.40.12 Verapamil4.6±2.54.6±2.10.99 L-NMMA0.83±0.240.80±0.220.53 Norepinephrine0.62±0.210.65±0.180.48These data demonstrate that in a young male population, the T allele of the MTHFR gene polymorphism is associated with augmented vascular responses to acetylcholine and nitroprusside, and this is confined to those with the lowest plasma folate level. These data are in agreement with others that in normal subjects the MTHFR genotype does not influence homocysteine and does not correlate with endothelial dysfunction, which is a recognized predictor of future vascular disease. Indeed, the T allele may in fact protect the endothelium in young normal subjects.1 Verhoef P, Hennekens CH, Malinow MR, Kok FJ, Willett WC, Stampfer MJ. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke. 1994; 25: 1924–1930.CrossrefMedlineGoogle Scholar2 Stampfer MJ, Malinow MR, Willett WC, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992; 268: 877–881.CrossrefMedlineGoogle Scholar3 Evans RW, Shaten BJ, Hempel JD, Cutler JA, Kuller LH. Homocyst(e)ine, and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol. 1997; 17: 1947–1953.CrossrefMedlineGoogle Scholar4 Alfthan G, Pekkanen J, Jauhiainen M, Pitkaniemi J, Karvone M, Tuomilehto J, Salonen JT, Ehnholm C. Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis. 1994; 106: 9–19.CrossrefMedlineGoogle Scholar5 Brattstrom L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation. 1998; 98: 2520–2526.CrossrefMedlineGoogle Scholar6 Kang SS, Wong PW, Bock HG, Horwitz A, Grix A. Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations. Am J Human Genetics. 1991; 48: 546–551.MedlineGoogle Scholar7 Adams M, Smith PD, Martin D, Thompson JR, Lodwick D, Samani NJ. Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction. QJM. 1996; 89: 437–444.CrossrefMedlineGoogle Scholar8 Kang SS, Passen EL, Ruggie N, Wong PW, Sora H. Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease. Circulation. 1993; 88: 1463–1469.CrossrefMedlineGoogle Scholar9 Ma J, Stampfer MJ, Hennekens CH, Frosst P, Selhub J, Horsford J, Malinow MR, Willett WC, Rozen R. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation. 1996; 94: 2410–2416.CrossrefMedlineGoogle Scholar10 Demuth K, Moatti N, Hanon O, Benoit MO, Safar M, Girerd X. Opposite effects of plasma homocysteine and the methylenetetrahydrofolate reductase C677T mutation on carotid artery geometry in asymptomatic adults. Arterioscler Thromb Vasc Biol. 1998; 18: 1838–1843.CrossrefMedlineGoogle Scholar11 Butler R, Morris AD, Belch JJ, Hill A, Struthers AD. Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension. 2000; 35: 746–751.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Vallelunga A, Pegoraro V, Pilleri M, Biundo R, De Iuliis A, Marchetti M, Facchini S, Formento Dojot P and Antonini A (2013) The MTHFR C677T polymorphism modifies age at onset in Parkinson's disease, Neurological Sciences, 10.1007/s10072-013-1545-z, 35:1, (73-77), Online publication date: 1-Jan-2014. Brunner H, Cockcroft J, Deanfield J, Donald A, Ferrannini E, Halcox J, Kiowski W, L??scher T, Mancia G, Natali A, Oliver J, Pessina A, Rizzoni D, Rossi G, Salvetti A, Spieker L, Taddei S and Webb D (2005) Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension*, Journal of Hypertension, 10.1097/00004872-200502000-00001, 23:2, (233-246), Online publication date: 1-Feb-2005. Moat S, Lang D, McDowell I, Clarke Z, Madhavan A, Lewis M and Goodfellow J (2004) Folate, homocysteine, endothelial function and cardiovascular disease, The Journal of Nutritional Biochemistry, 10.1016/j.jnutbio.2003.08.010, 15:2, (64-79), Online publication date: 1-Feb-2004. Girelli D, Martinelli N, Pizzolo F, Friso S, Olivieri O, Stranieri C, Trabetti E, Faccini G, Tinazzi E, Pignatti P and Corrocher R (2003) The Interaction between MTHFR 677 C→T Genotype and Folate Status Is a Determinant of Coronary Atherosclerosis Risk, The Journal of Nutrition, 10.1093/jn/133.5.1281, 133:5, (1281-1285), Online publication date: 1-May-2003. Spence M, McGlinchey P, Patterson C, Belton C, Murphy G, McMaster D, Fogarty D, Evans A and McKeown P (2002) Family-based investigation of the C677T polymorphism of the methylenetetrahydrofolate reductase gene in ischaemic heart disease, Atherosclerosis, 10.1016/S0021-9150(02)00239-3, 165:2, (293-299), Online publication date: 1-Dec-2002. January 2002Vol 22, Issue 1 Advertisement Article InformationMetrics https://doi.org/10.1161/atvb.22.1.193PMID: 11788482 Originally publishedMarch 15, 2018 PDF download Advertisement