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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:193.)
© 2002 American Heart Association, Inc.

Letters to the Editor

The 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; Allan 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

To 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)

View this table: [in this window] [in a new window]   Table 1. Blood Flow Responses to Infused Agents and Demographic Details by Genotype

We 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)

View this table: [in this window] [in a new window]   Table 2. Effects of Folate Quartile on Blood Flow Ratio by MTHFR Genotype

These 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.

References

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2. 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.[Abstract]
3. 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.[Abstract/Free Full Text]
4. 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.[CrossRef][Medline] [Order article via Infotrieve]
5. 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.[Abstract/Free Full Text]
6. 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.[Medline] [Order article via Infotrieve]
7. 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.[Abstract]
8. Kang SS, Passen EL, Ruggie N, Wong PW, Sora H. Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease. Circulation. 1993; 88: 1463–1469.[Abstract/Free Full Text]
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10. 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.[Abstract/Free Full Text]
11. 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.[Abstract/Free Full Text]

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