This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brattström, L. Articles by Brudin, L. Search for Related Content PubMed PubMed Citation Articles by Brattström, L. Articles by Brudin, L.

(Circulation. 1998;98:2520-2526.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Common Methylenetetrahydrofolate Reductase Gene Mutation Leads to Hyperhomocysteinemia but Not to Vascular Disease

The Result of a Meta-Analysis

Lars Brattström, MD, PhD; David E. L. Wilcken, MD, FRCP, FRACP; John Öhrvik, PhD; Lars Brudin, MD, PhD

From the Departments of Medicine (L. Brattström) and Clinical Physiology (L. Brudin), County Hospital, Kalmar, Sweden; Department of Cardiovascular Medicine (D.E.L.W.), University of New South Wales, The Prince Henry and Prince of Wales Hospitals, Sydney, Australia; and Department of Statistics (J.Ö.), The Swedish University of Agricultural Sciences, Uppsala, Sweden.

Correspondence to Assoc Prof Lars Brattström, Department of Medicine, Kalmar Hospital, S-391 85 Kalmar, Sweden. E-mail lars.brattstrom{at}alinks.se

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—The results of retrospective and prospective case-control studies have clearly established that mild elevations of the plasma homocysteine level are associated with increased risk of coronary, cerebral, and peripheral vascular disease. Recently, a mutation (677CT) was identified in the methylenetetrahydrofolate reductase (MTHFR) gene that results in reduced folate-dependent enzyme activity and reduced remethylation of homocysteine to methionine. Mutant homozygotes (TT genotype) constitute 12% of the white population and frequently have mildly elevated circulating homocysteine. Therefore, it seems likely that they would also be at increased risk of vascular disease. A number of studies have investigated this during the past 3 years, and the present article evaluates the results in a meta-analysis.

Methods and Results—We identified 13 studies in which there were measurements of plasma homocysteine in relation to the 3 genotypes (TT, CT, and CC) and 23 case-control studies comprising 5869 genotyped cardiovascular disease patients (mostly coronary artery disease) and 6644 genotyped control subjects. Those bearing the TT genotype had plasma homocysteine concentrations 2.6 µmol/L (25%) higher than those with the CC genotype. However, there was no difference between patients and control subjects either in the frequency of mutant alleles (T) (34.3% versus 33.8%) or the TT genotype (11.9% versus 11.7%). In the analysis of the 23 studies, the relative risk (OR) of vascular disease associated with the TT genotype was 1.12 (95% CI, 0.92 to 1.37).

Conclusions—We conclude that although the C677T/MTHFR mutation is a major cause of mild hyperhomocysteinemia, the mutation does not increase cardiovascular risk. Our findings suggest that the mild hyperhomocysteinemia found frequently in vascular disease patients is not causally related to the pathogenesis of the vascular disease.

Key Words: homocysteine • methylenetetrahydrofolate reductase • risk factors • coronary disease

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
There is increased interest in mild hyperhomocysteinemia as an important common risk factor for cardiovascular disease that can easily be normalized with folic acid therapy.^{1 2} The basis of this interest stems from the knowledge that certain rare inborn errors of metabolism, generally called homocystinurias, lead to severe hyperhomocysteinemia (>150 µmol/L), arteriosclerosis, and life-threatening arterial and venous thromboembolic events in the very young.³ This has led to many studies of mild homocysteine elevation in the adult general population, and the results of these suggest that even slight elevations of total plasma homocysteine (>15 µmol/L) concentrations are associated with increased risk of myocardial infarction, stroke, peripheral arterial disease, and venous thrombosis.^{4 5 6 7 8 9 10 11 12} Furthermore, results of cross-sectional and retrospective and prospective case-control studies have found a graded relationship between plasma homocysteine levels and the risk or severity of cardiovascular disease, suggesting that the relationship is causal.^{2 8 9 10 12}

Homocysteine is methylated to methionine by the transfer of the methyl group of methyltetrahydrofolate, which is formed by reduction of the methylene group of methylenetetrahydrofolate in a reaction catalyzed by methylenetetrahydrofolate reductase (MTHFR).¹ Genetic deficiency of MTHFR is one of the rare homocystinurias leading to severe hyperhomocysteinemia and cardiovascular disease in the very young.¹ In 1988, Kang et al¹³ described a thermolabile variant of MTHFR that is associated with decreased enzyme activity and mildly elevated plasma homocysteine levels. The responsible mutation in the MTHFR gene, a CT substitution at base pair 677 leading to the exchange of an alanine to a valine, was identified by Frosst et al¹⁴ in 1995. They found that the mutation was present in 35% of alleles and that mutant homozygotes (TT genotype, 12% of the population) had significantly higher mean plasma homocysteine concentrations than those not carrying the mutant allele (CC genotype). Consequently, this common C677T/MTHFR mutation was considered likely to be a common genetic risk factor for cardiovascular disease, and a number of studies were undertaken to explore this possibility.

In the present study, we present a meta-analysis of the combined results of the first 13 studies^{14 15 16 17 18 19 20 21 22 23 24 25 26} that have documented plasma homocysteine concentrations in relation to the 3 genotypes TT, CT, and CC and of the first 23 studies^{18 19 20 21 22 23 24 25 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41} that have explored the risk of cardiovascular disease in the TT versus the CC genotypes.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Through Medline, Current Contents, and abstracts books from congresses, we identified 25 reports^{18 19 20 21 22 23 24 25 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43} on the frequency of the C677T/MTHFR mutation in cardiovascular disease patients and control subjects. Eighteen of these studies have been published as full articles, 6 as letters to editors, and 1 as an abstract. Two of these reports were not included in the meta-analysis, 1 because of uncertainty regarding the ethnic origin of patients and control subjects⁴² and 1 because of lack of an adequate control group.⁴³ The relationship between the C677T/MTHFR genotypes and plasma concentration of total homocysteine was evaluated in 8 of these studies^{18 19 20 21 22 23 24 25} and also in 5 others.^{14 15 16 17 26} Information about relationships between total homocysteine and genotypes according to folate status was available in 5 studies.^{16 17 20 22 24}

The numbers of C677T/MTHFR mutant homozygotes (TT genotype), mutant heterozygotes (CT genotype), and normal homozygotes (CC genotype=wild type) in patients and control subjects from each study are shown in Table 1. In 2 studies, the genotype frequency was not reported, and we obtained these data from the authors.^{34 37}

View this table: [in this window] [in a new window]   Table 1. Numbers and Frequencies of the 3 Different C677T/MTHFR Genotypes (TT Genotype=Mutant Homozygotes, CT Genotype=Mutant Heterozygotes, and CC Genotype=Normal Homozygotes) in 23 Studies of Patients With Cardiovascular Disease and Control Subjects

We used the data shown in the tables to estimate the relative risks for cardiovascular disease by calculating the ORs and corresponding 95% CIs. In each study, the ORs were calculated for cardiovascular disease in the TT versus CC genotypes by use of formulas published elsewhere.⁴⁴ The ORs for the 23 studies were tested for homogeneity by the Breslow-Day test.⁴⁵ The result was highly significant (P<0.0001), indicating heterogeneity between studies. To allow for heterogeneity between studies, a random-effect model was assessed as follows. Let _i denote the true log OR for study i. Then an unbiased estimate of _i is _i=log (a_id_i/b_ic_i), where a_i, b_i, c_i, and d_i are the number of TT cases, TT controls, CC cases, and CC controls, respectively, in study i. The asymptotic variance of _i is given by Avar(_i)=1/a_i+1/b_i+1/c_i+1/d_i. Assume that the _i:s are normally distributed with mean and variance ². The between-study variance ² is estimated as ²=max{0, [-(k-1)]/(w_i-w_i²/w_i)}, where k is the number of studies, w_i=1/Avar(_i), and =w_i(_i-w_ii/w_i).² The common OR, exp(), can now be estimated as exp(), where =w_i*_i/w_i* and w_i*=1/(Avar _i+²). Because the asymptotic variance of is Avar()=1/w_i*, an approximate 95% CI for the common OR is given by [exp(-1.961/w_i*),exp(+1.961/w_i*)].

	Results

Top Abstract Introduction Methods Results Discussion References

 
In the 23 studies included in the meta-analysis,^{18 19 20 21 22 23 24 25 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41} the C677T/MTHFR genotype was available in a total of 5869 patients with cardiovascular disease and in 6644 control subjects (Table 1). The prevalence of the TT genotype varied between 5.4% and 16.0% in the different groups of control subjects and between 6.5% and 29.7% in the different groups of patients. In all studies combined, the distributions of the different genotypes and the allele frequency were almost identical in patients and control subjects (Table 1). The TT genotype was present in 11.9% of the patients and in 11.7% of the control subjects.

The OR as an estimate of relative cardiovascular risk in the TT versus CC genotypes was >1.0 in 11 and <1.0 in 12 studies (Figure). In 4 studies, both the ORs and the 95% CIs were >1.0.^{18 27 28 29 30 31 36} In two^{18 27} of these 4, the TT genotype frequencies in control subjects were only 5.4% (6 of 111) and 6.7% (7 of 105). These frequencies are considerably lower than those found in other larger groups from the same populations: 8.5% (106 of 1250, Dutch) and 11.5% (72 of 625, Irish), respectively.^{17 23} There was a considerable heterogeneity of the ORs of the 23 studies. After adjustment for heterogeneity, the combined OR of all 23 studies for relative vascular risk in TT homozygotes versus normal CC homozygotes was 1.12 (95% CI, 0.92 to 1.37) (Figure). The corresponding combined OR for the 17 studies* that included only patients with coronary heart disease (CHD in Table 1) was 1.11 (95% CI, 0.91 to 1.37).

View larger version (34K): [in this window] [in a new window]   Figure 1. ORs and 95% CIs estimating relative risk of cardiovascular disease in C677T/MTHFR homozygotes (TT genotype) versus normal homozygotes (CC genotype) in 23 different studies (Reference No.) of patients with cardiovascular disease and control subjects. Summary OR is adjusted for heterogeneity between studies.

The results of 13 studies^{14 15 16 17 18 19 20 21 22 23 24 25 26} of total plasma homocysteine concentrations in the different C667T/MTHFR genotypes are shown in Table 2. They establish that the TT genotype has significantly higher mean homocysteine concentration than the CT and CC genotypes. On average, those with the TT genotype have 2.6 µmol/L or 25% higher mean total plasma homocysteine concentration than those with the CC genotype. Table 3 shows that the TT genotype is considerably more frequent among those with elevated total plasma homocysteine than in the whole population.⁴⁶

View this table: [in this window] [in a new window]   Table 2. Total Plasma Homocysteine in 13 Different Studies in Relation to the C677T/MTHFR Genotypes (TT Genotype=Mutant Homozygotes, CT Genotype=Mutant Heterozygotes, CC Genotype=Normal Homozygotes

View this table: [in this window] [in a new window]   Table 3. Frequency of the C677T/MTHFR TT Genotype in Subjects With Elevated Plasma Homocysteine Concentrations and in the Whole Population

Finally, Table 4 shows that the phenotypic expression of elevated total plasma homocysteine in those with the TT genotype was most pronounced in homozygotes with folate levels below the median or in the lowest quartile of serum folate. In subjects with higher folate levels, total plasma homocysteine concentrations between the different genotypes are not different.

View this table: [in this window] [in a new window]   Table 4. Plasma Homocysteine (µmol/L) in Relation to Folate and C677T/MTHFR Genotypes

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This meta-analysis of the distribution of the common C677T/MTHFR gene mutation genotypes in patients with cardiovascular disease and in control subjects shows that although those bearing the TT genotype have on average 25% higher mean total plasma homocysteine concentration than the normal wild CC genotype, they have no overall increased risk of cardiovascular disease generally or of coronary heart disease in particular. The power of this analysis is such that any important increased risk would have been detected. Moreover, in developed countries, cardiovascular disease is the main cause of death. Yet, in a meta-analysis of 4 studies of the C677T/MTHFR mutation in elderly and newborn or young subjects, the OR representing the likelihood of those with the TT genotype attaining old age relative to those with the CC genotype was 0.87 (95% CI, 0.69 to 1.11).⁴⁷ This is not compatible with the mutation being a major risk factor for premature cardiovascular death and is in accord with the findings of the present meta-analysis.

There is strong evidence that mild hyperhomocysteinemia, in the range found in the TT genotype, is a risk factor for atherosclerotic and thrombotic cardiovascular disease.^{1 2 4 5 6 7 8 9 10 11 12} The relationship has been considered to be causal, and homocysteine-lowering therapy with folic acid proposed to reduce the risk.² If mild hyperhomocysteinemia itself causes vascular injury and cardiovascular disease, it would be logical to consider that any cause of long-standing mild hyperhomocysteinemia (ie, TT genotype) would also increase cardiovascular risk. This led to the studies included in the present meta-analysis. As an explanation for the negative results found in many of these studies, it was argued that because increased plasma homocysteine in TT homozygotes is folate-dependent, caution is warranted in drawing conclusions from reports lacking adequate information on folate and homocysteine levels.⁴⁸ Therefore, we assessed published data on homocysteine and the homocysteine-folate relationship in relation to C677T/MTHFR genotypes (Tables 2 through 4).

These combined data clearly establish that the TT genotype is associated with elevated mean plasma homocysteine levels in probably well-nourished groups of American, Canadian, Dutch, Norwegian, Italian, and Irish subjects and that high homocysteine levels are confined primarily to those TT homozygotes with folate levels below the median or in the lowest quartile of serum or plasma folate. Depending on the chosen cutoff point for hyperhomocysteinemia, the combined data also show that 21% to 73% of hyperhomocysteinemic subjects are TT homozygotes. Thus, the TT genotype is a major cause of mild hyperhomocysteinemia in these populations.

The frequently quoted prospective US Physicians Health Study⁷ provides an example of the discrepancy between cardiovascular risk attributable to homocysteine and the C677T/MTHFR mutation. It showed a minimal but significant excess (0.6 µmol/L) of plasma homocysteine in those who subsequently developed myocardial infarction compared with matched control subjects (11.1 versus 10.5 µmol/L). The relative risk for myocardial infarction for the highest 5% of the homocyst(e)ine distribution (>15.8 µmol/L) versus the bottom 90% was significant: 3.4 (95% CI, 1.3 to 8.8). In a later report²⁰ on essentially the same patients and control subjects, the TT genotype was present in 21% of hyperhomocysteinemic subjects (>15.8 µmol/L) and in 12% of normohomocysteinemic subjects, and the mean plasma homocysteine was 2.0 µmol/L higher in TT homozygotes than in CC homozygotes (12.6 versus 10.6 µmol/L). Nonetheless, the TT genotype was found less frequently in patients than in control subjects (11.3% versus 13.4%), and it was not associated with risk of myocardial infarction (OR, 0.84; 95% CI, 0.50 to 1.42). In the Health Professionals Follow-up Study,³⁷ the TT genotype was present in 12.2% of men with coronary artery disease (n=280) or myocardial infarction (n=220) and in 14.2% of 500 male control subjects. For the TT genotype, the OR of coronary artery disease was 1.04 (95% CI, 0.67 to 1.62) and, surprisingly, the OR for myocardial infarction was significantly reduced (OR, 0.49; 95% CI, 0.28 to 0.87). Moreover, the TT genotype was not positively associated with risk of coronary heart disease among men with low intake of folate.

As an extension of the results of this meta-analysis, which excludes an association between increased cardiovascular risk and the TT genotype, itself a major cause of mild hyperhomocysteinemia, our findings argue against there being a causal relationship between mildly elevated plasma homocysteine and increased cardiovascular risk. What, then, is the explanation for the frequent finding of mild hyperhomocysteinemia in patients who have or will develop cardiovascular disease? The Hordaland Study,⁴⁹ the largest population-based study (7591 men and 8585 women, 40 to 67 years of age) of the relationship between plasma homocysteine and established risk factors for cardiovascular disease, has provided important data relevant to this question. The study showed that elevated plasma homocysteine was strongly and positively associated with major components of the cardiovascular risk profile, ie, male sex, age, smoking, blood pressure, elevated total cholesterol, and lack of exercise. Such relationships may well account for the frequent finding of elevated plasma homocysteine in patients with cardiovascular disease. Relatively small case-control studies may not have the statistical power to adjust for and fully eliminate the effects of these other risk factors on plasma homocysteine concentration.

Another possible cause of elevated plasma homocysteine in cardiovascular disease is mildly impaired renal function resulting from both hypertension and atherosclerosis. Under physiological conditions, the kidneys are estimated to be responsible for 70% of plasma homocysteine clearance, and in renal insufficiency, when clearance is reduced, plasma homocysteine concentration is considerably increased.^{50 51} Renal function is a major determinant of plasma homocysteine concentration, because there is a strong positive correlation between the levels of plasma homocysteine and serum creatinine in both healthy subjects and patients with cardiovascular disease.^{1 10 52 53} The likelihood is that patients with both subclinical and clinical atherosclerotic vascular disease on average have renal function that is slightly reduced compared with that of control subjects. This may also contribute to the finding of higher plasma homocysteine concentrations in patients than in normal control subjects in both prospective nested and retrospective case-control studies and of a graded relationship between plasma homocysteine and severity of atherosclerosis.

In conclusion, although the markedly elevated homocysteine levels (>150 µmol/L) found in the inborn errors leading to homocystinuria undoubtedly are associated with vascular disease and reducing these high concentrations reduces cardiovascular risk,^{54 55} it is very doubtful whether the small homocysteine elevations (>15 µmol/L) found in cardiovascular disease patients have directly contributed to the development of their disease. The common MTHFR mutation is accompanied by the small homocysteine elevations also found in vascular patients, but the present analysis establishes that the mutation is not associated with increased cardiovascular risk. We suggest that the modest homocysteine increase found in patients with cardiovascular disease is an epiphenomenon, a consequence of the effects of the well-established standard risk factors for vascular disease and renal function, and that it is not directly causal.

	Footnotes

 
¹ References 19, 20, 22–25, 27–30, 32–37, and 39.

Received April 1, 1998; revision received August 7, 1998; accepted August 13, 1998.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Ueland PM, Refsum H, Brattström L. Plasma homocysteine and cardiovascular disease. In: Francis RB Jr, ed. Atherosclerotic Cardiovascular Disease, Hemostasis and Endothelial Function. New York, NY: Marcel Dekker Inc; 1992:183–236.

2. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049–1057.[Abstract/Free Full Text]

3. Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995:1279–1327.

4. Wilcken DEL, Wilcken B. The pathogenesis of coronary artery disease: a possible role for methionine metabolism. J Clin Invest. 1976;57:1079–1082.

5. Brattström LE, Hardebo JE, Hultberg BL. Moderate homocysteinemia: a possible risk factor for arteriosclerotic cerebrovascular disease. Stroke. 1984;15:1012–1015.[Abstract/Free Full Text]

6. Boers GHJ, Smals AGH, Trijbels FJM, Fowler B, Bakkeren JAJM, Schoonderwaldt HC, Kleijer WJ, Kloppenborg PWC. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med. 1985;313:709–715.[Abstract]

7. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA. 1992;268:877–881.[Abstract/Free Full Text]

8. Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PWF, Belanger AJ, O'Leary DH, Wolf PA, Schaefer EJ, Rosenberg I. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995;332:286–291.[Abstract/Free Full Text]

9. Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug JE. Serum total homocysteine and coronary artery disease. Int J Epidemiol. 1995;24:704–709.[Abstract/Free Full Text]

10. Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-age British men. Lancet. 1995;346:1395–1398.[Medline] [Order article via Infotrieve]

11. den Heijer M, Koster T, Blom HJ, Bos GMJ, Briet E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med. 1996;334:759–762.[Abstract/Free Full Text]

12. Graham IM, Daly LE, Refsum H, Robinson K, Brattström LE, Ueland PM, Palma-Reis RJ, Boers GHJ, Sheahan RG, Israelsson B, Uiterwaal CS, Meleady R, McMaster D, Verhoef P, Witteman J, Rubba P, Bellet H, Wautrecht JC, de Valk HW, Sales Lúis AC, Parrot-Roulaud FM, Soon Tan K, Higgins I, Garcon D, Medrano MJ, Candito M, Evans AE, Andria G, for The European Concerted Action Project. Plasma homocysteine as a risk factor for vascular disease. JAMA. 1997;277:1775–1781.[Abstract/Free Full Text]

13. Kang SS, Zhou J, Wong PWK, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet. 1988;43:414–421.[Medline] [Order article via Infotrieve]

14. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, van den Heuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111–113.[Medline] [Order article via Infotrieve]

15. van der Put NMJ, Steegers-Theunissen RPM, Frosst P, Trijbels FJM, Eskes TKAB, van den Heuvel LP, Mariman ECM, den Heyer M, Rozen R, Blom HJ. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet. 1995;346:1070–1071.[Medline] [Order article via Infotrieve]

16. Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93:7–9.[Abstract/Free Full Text]

17. Harmon DL, Woodside JV, Yarnell JWG, McMaster D, Young IS, McCrum EE, Gey KF, Whitehead AS, Evans AE. The common "thermolabile" variant of methylenetetrahydrofolate reductase is a major determinant of mild hyperhomocysteinemia. Q J Med. 1996;89:571–577.[Abstract/Free Full Text]

18. Kluijtmans LAJ, van den Heuvel PWJ, Boers GHJ, Frosst P, Stevens EMB, van Oost BA, den Heijer M, Trijbels FJM, Rozen R, Blom HJ. Molecular genetics analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;58:35–41.[Medline] [Order article via Infotrieve]

19. Schmitz C, Lindpaintner K, Verhoef P, Gaziano JM, Buring J. Genetic polymorphism of methylenetetrahydrofolate reductase and myocardial infarction: a case-control study. Circulation. 1996;94:1812–1814.[Abstract/Free Full Text]

20. Ma J, Stampfer MJ, Hennekens CH, Frosst P, Selhub J, Horsford J, Malinow R, Willett WC, Rozen R. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation. 1996;94:2410–2416.[Abstract/Free Full Text]

21. Deloughery TG, Evans A, Sadeghi A, McWilliams J, Henner WD, Taylor LM, Press RD. Common mutation in methylenetetrahydrofolate reductase: correlation with homocysteine metabolism and late-onset vascular disease. Circulation. 1996;94:3074–3078.[Abstract/Free Full Text]

22. Verhoef P, Kok FJ, Kluijtmans LAJ, Blom HJ, Refsum H, Ueland PM, Kruyssen HACM. The 677CT mutation in the methylenetetrahydrofolate reductase gene: associations with plasma total homocysteine levels and risk for coronary atherosclerotic disease. Atherosclerosis. 1997;132:105–113.[Medline] [Order article via Infotrieve]

23. Kluijtmans LAJ, Kastelein JJP, Lindemans J, Boers GHJ, Heil SG, Bruschke AVG, Jukema JW, Vandenheuvel LPWJ, Trijbels FJM, Boerma GJM, Verheugt FWA, Willems F, Blom HJ. Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation. 1997;96:2573–2577.[Abstract/Free Full Text]

24. Christensen B, Frosst P, Lussier-Cacan S, Selhub J, Goyette P, Rosenblatt DS, Genest J, Rozen R. Correlation of a common mutation in the methylenetetrahydrofolate reductase gene with plasma homocysteine in patients with premature coronary artery disease. Arterioscler Thromb Vasc Biol. 1997;17:569–573.[Abstract/Free Full Text]

25. Schwartz SM, Siscovick DS, Malinow MR, Rosendaal FR, Beverly RK, Hess DL, Psaty BM, Longstreth WT Jr, Koepsell TD, Raghunathan TE, Reitsma PH. Myocardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene. Circulation. 1997;96:412–417.[Abstract/Free Full Text]

26. Legnani C, Palareti G, Grauso F, Sassi S, Grossi G, Piazzi S, Bernardi F, Marchetti G, Ferraresi P, Coccheri S. Hyperhomocyst(e)inemia and a common methylenetetrahydrofolate reductase mutation (Ala²²³Val MTHFR) in patients with inherited thrombophilic coagulation defects. Arterioscler Thromb Vasc Biol. 1997;17:2924–2929.[Abstract/Free Full Text]

27. Gallagher PM, Meleady R, Shields DC, Soon Tan K, McMaster D, Rozen R, Evans A, Graham IM, Whitehead AS. Homocysteine and risk of premature coronary heart disease: evidence for a common gene mutation. Circulation. 1996;94:2154–2158.[Abstract/Free Full Text]

28. Adams M, Smith PD, Martin D, Thomson JR, Lodwick D, Samani NJ. Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction. Q J Med. 1996;89:437–444.[Abstract/Free Full Text]

29. Izumi M, Iwai N, Ohmichi N, Nakamura Y, Shimoike H, Kinoshita M. Molecular variant of 5,10-methylenetetrahydrofolate reductase is a risk factor of ischemic heart disease in the Japanese population. Atherosclerosis. 1996;121:293–294.[Medline] [Order article via Infotrieve]

30. Wilcken DEL, Wang XL, Sim AS, McCredie M. Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C₆₇₇T mutation. Arterioscler Thromb Vasc Biol. 1996;16:878–882.[Abstract/Free Full Text]

31. de Franchis R, Mancini FP, D'Angelo A, Sebastio G, Fermo I, de Stefano V. Elevated total plasma homocysteine and 677CT mutation of the 5,10-methylenetetrahydrofolate reductase gene in thrombotic vascular disease. Am J Hum Genet. 1996;59:262–264.[Medline] [Order article via Infotrieve]

32. Narang R, Callaghan G, Haider AW, Davies GJ, Tuddenham EGD. Methylenetetrahydrofolate reductase mutation and coronary artery disease. Circulation. 1996;94:2322–2323.

33. Brulhart MC, Dussoix P, Ruiz J, Passa P, Froguel P, James RW. The (Ala-Val) mutation of methylenetetrahydrofolate reductase as a genetic risk factor for vascular disease in non-insulin-dependent diabetic patients. Am J Hum Genet. 1997;60:228–229.[Medline] [Order article via Infotrieve]

34. van Bockxmeer FM, Mamotte CDS, Vasikaran SD, Taylor RR. Methylenetetrahydrofolate reductase gene and coronary artery disease. Circulation. 1997;95:21–23.[Abstract/Free Full Text]

35. Brugada R, Marian AJ. A common mutation in methylenetetrahydrofolate reductase gene is not a major risk of coronary artery disease or myocardial infarction. Atherosclerosis. 1997;128:107–112.[Medline] [Order article via Infotrieve]

36. Morita H, Taguchi J, Kurihara H, Kitaoka M, Kaneda H, Kurihara Y, Maemura K, Shindo T, Minamino T, Ohno M, Yamaoki K, Ogasawara K, Aizawa T, Suzuki S, Yazaki Y. Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation. 1997;95:2032–2036.[Abstract/Free Full Text]

37. Verhoef P, Rimm EB, Hunter DJ, Chen J, Willett WC, Kelsey K, Stampfer MJ. Methylenetetrahydrofolate reductase polymorphism, diet, and risk of coronary heart disease among men. 16th International Congress of Nutrition. July 27–August 1, 1997, Montreal, Canada. Abstract PW3.12.

38. Tosetto A, Missiaglia E, Frezzato M, Rodeghiero F, the VITA Project. C677T mutation in the methylene-tetrahydrofolate reductase gene and risk of venous thromboembolism. Br J Haematol. 1997;97:804–806.[Medline] [Order article via Infotrieve]

39. Malinow MR, Nieto FJ, Kruger WD, Duell PB, Hess DL, Gluckman RA, Block PC, Holzgang CR, Anderson PH, Seltzer D, Upson B, Lin QR. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol. 1997;17:1157–1162.[Abstract/Free Full Text]

40. Markus H, Ali N, Swaminathan R, Sankaralingam A, Molloy J, Powell J. A common polymorphism in the methylenetetrahydrofolate reductase gene, homocysteine, and ischemic cerebrovascular disease. Stroke. 1997;28:1739–1743.[Abstract/Free Full Text]

41. Salden A, Keeney S, Hay CRM, Cumming AM. The C677T MTHFR variant and the risk of venous thrombosis. Br J Haematol. 1997;99:464–472.[Medline] [Order article via Infotrieve]

42. Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677Val in the methylenetetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. Thromb Haemost. 1997;77:818–821.[Medline] [Order article via Infotrieve]

43. Anderson JL, King GJ, Thomson MJ, Todd M, Bair TL, Muhlestein JB, Carlquist JF. A mutation in the methylenetetrahydrofolate reductase gene is not associated with increased risk for coronary artery disease or myocardial infarction. J Am Coll Cardiol. 1997;30:1206–1211.[Abstract]

44. Sandercock P. The odds ratio: a useful tool in neurosciences. J Neurol Neurosurg Psychiatry. 1989;52:817–820.[Abstract/Free Full Text]

45. Agresti A. An Introduction to Categorical Data Analysis. New York, NY: John Wiley & Sons; 1996:63–64.

46. Guttormsen AB, Ueland PM, Nesthus I, Nygård O, Schneede J, Vollset SE, the Hordaland homocysteine study. Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (40 µmol/L). J Clin Invest. 1996;98:2174–2183.[Medline] [Order article via Infotrieve]

47. Brattström L, Zhang Y, Hurtig M, Refsum H, Östensson S, Fransson L, Jonés K, Landgren F, Brudin L, Ueland PM. A common methylenetetrahydrofolate reductase gene mutation (C677T/MTHFR) and longevity. Atherosclerosis. In press.

48. Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost. 1997;78:523–526.[Medline] [Order article via Infotrieve]

49. Nygård O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, Ueland PM, Kvåle G, the Hordaland Homocysteine Study. Total plasma homocysteine and cardiovascular risk profile. JAMA. 1995;274:1526–1533.[Abstract/Free Full Text]

50. Guttormsen AB, Ueland PM, Svarstad E, Refsum H. Kinetic basis of hyperhomocysteinemia in patients with chronic renal failure. Kidney Int. 1997;52:495–502.[Medline] [Order article via Infotrieve]

51. Arnadottir M, Hultberg B, Nilsson-Ehle P, Thysell H. The effect of reduced glomerular filtration rate on plasma total homocysteine concentration. Scand J Lab Invest. 1996;56:41–46.

52. Brattström L, Lindgren A, Israelsson B, Andersson A, Hultberg B. Homocysteine and cysteine: determinants of plasma levels in middle-aged and elderly subjects. J Intern Med. 1994;236:633–641.[Medline] [Order article via Infotrieve]

53. Brattström L, Lindgren A, Israelsson B, Malinow MR, Norrving B, Upson B, Hamfelt A. Hyperhomocysteinemia in stroke: prevalence, cause, and relationships to type of stroke and stroke risk factors. Eur J Clin Invest. 1992;22:214–221.[Medline] [Order article via Infotrieve]

54. Mudd HS, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GHJ, Bromberg IL, Cerone R, Fowler B, Gröbe H, Schmidt H, Schweitzer L. The natural history of homocystinuria due to cystathionine ß-synthase deficiency. Am J Hum Genet. 1985;37:1–31.[Medline] [Order article via Infotrieve]

55. Wilcken DEL, Wilcken B. The natural history of vascular disease in homocystinuria and the effect of treatment. J Inherit Metab Dis. 1997;20:295–300.In a meta-analysis, we assessed the association between the C677T mutation of the MTHFR gene, plasma homocysteine, and cardiovascular risk. Although in 13 studies, those with the mutant TT genotype had a mean homocysteine level 2.6 µmol/L (25%) higher than those with the wild CC genotype, the mutant TT genotype frequency in 23 case-control studies was similar in 5869 patients with vascular disease (11.9%) and 6644 control subjects (11.7%); and compared with the CC genotype, the TT genotype was not associated with increased cardiovascular risk (OR, 1.12; 95% CI, 0.92 to 1.37). These results suggest that mild hyperhomocysteinemia is not causally related to the pathogenesis of cardiovascular disease.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				I. Zak, B. Sarecka-Hujar, I. Kopyta, E. Emich-Widera, E. Marszal, J. Wendorff, and J. Jachowicz-Jeszka The T Allele of the 677C>T Polymorphism of Methylenetetrahydrofolate Reductase Gene is Associated With an Increased Risk of Ischemic Stroke in Polish Children J Child Neurol, October 1, 2009; 24(10): 1262 - 1267. [Abstract] [PDF]

				R. Bourouba, B. Houcher, F. Djabi, Y. Egin, and N. Akar The Prevalence of Methylenetetrahydrofolate Reductase 677 C-T, Factor V 1691 G-A, and Prothrombin 20210 G-A Mutations in Healthy Populations in Setif, Algeria Clinical and Applied Thrombosis/Hemostasis, October 1, 2009; 15(5): 529 - 534. [Abstract] [PDF]

				V. Ganji and M. R. Kafai Demographic, Lifestyle, and Health Characteristics and Serum B Vitamin Status Are Determinants of Plasma Total Homocysteine Concentration in the Post-Folic Acid Fortification Period, 1999-2004 J. Nutr., February 1, 2009; 139(2): 345 - 352. [Abstract] [Full Text] [PDF]

				J. S. Elkins, S. C. Johnston, E. Ziv, D. Kado, J. A. Cauley, and K. Yaffe Methylenetetrahydrofolate Reductase C677T Polymorphism and Cognitive Function in Older Women Am. J. Epidemiol., September 15, 2007; 166(6): 672 - 678. [Abstract] [Full Text] [PDF]

				S. Zammit, S. Lewis, D. Gunnell, and G. D. Smith Schizophrenia and Neural Tube Defects: Comparisons From an Epidemiological Perspective Schizophr Bull, July 1, 2007; 33(4): 853 - 858. [Abstract] [Full Text] [PDF]

				A. S Wierzbicki Homocysteine and cardiovascular disease: a review of the evidence Diabetes and Vascular Disease Research, June 1, 2007; 4(2): 143 - 149. [Abstract] [PDF]

				F. Gemignani, S. Landi, N. Szeszenia-Dabrowska, D. Zaridze, J. Lissowska, P. Rudnai, E. Fabianova, D. Mates, L. Foretova, V. Janout, et al. Development of lung cancer before the age of 50: the role of xenobiotic metabolizing genes Carcinogenesis, June 1, 2007; 28(6): 1287 - 1293. [Abstract] [Full Text] [PDF]

				P. I. Holm, S. Hustad, P. M. Ueland, S. E. Vollset, T. Grotmol, and J. Schneede Modulation of the Homocysteine-Betaine Relationship by Methylenetetrahydrofolate Reductase 677 C->T Genotypes and B-Vitamin Status in a Large-Scale Epidemiological Study J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1535 - 1541. [Abstract] [Full Text] [PDF]

				T. Costacou, Y. Chang, R. E. Ferrell, and T. J. Orchard Identifying Genetic Susceptibilities to Diabetes-related Complications among Individuals at Low Risk of Complications: An Application of Tree-Structured Survival Analysis Am. J. Epidemiol., November 1, 2006; 164(9): 862 - 872. [Abstract] [Full Text] [PDF]

				H. McNulty, L. R. C. Dowey, J.J. Strain, M. Ward, L. B. McAnena, J. P. Hughes, M. Hannon-Fletcher, A. Dunne, A. M. Molloy, and J. M. Scott Response to Letter Regarding Article, "Riboflavin Lowers Homocysteine in Individuals Homozygous for the MTHFR 677C->T Polymorphism" Circulation, July 25, 2006; 114(4): e66 - e66. [Full Text] [PDF]

				L. B. Goldstein, R. Adams, M. J. Alberts, L. J. Appel, L. M. Brass, C. D. Bushnell, A. Culebras, T. J. DeGraba, P. B. Gorelick, J. R. Guyton, et al. Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline. Circulation, June 20, 2006; 113(24): e873 - e923. [Abstract] [Full Text] [PDF]

				J. Selhub The Many Facets of Hyperhomocysteinemia: Studies from the Framingham Cohorts J. Nutr., June 1, 2006; 136(6): 1726S - 1730S. [Abstract] [Full Text] [PDF]

				L. B. Goldstein, R. Adams, M. J. Alberts, L. J. Appel, L. M. Brass, C. D. Bushnell, A. Culebras, T. J. DeGraba, P. B. Gorelick, J. R. Guyton, et al. Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline. Stroke, June 1, 2006; 37(6): 1583 - 1633. [Abstract] [Full Text] [PDF]

				H. McNulty, L. R. C. Dowey, J.J. Strain, A. Dunne, M. Ward, A. M. Molloy, L. B. McAnena, J. P. Hughes, M. Hannon-Fletcher, and J. M. Scott Riboflavin Lowers Homocysteine in Individuals Homozygous for the MTHFR 677C->T Polymorphism Circulation, January 3, 2006; 113(1): 74 - 80. [Abstract] [Full Text] [PDF]

				A. Pastore, S. De Angelis, S. Casciani, R. Ruggia, G. Di Giovamberardino, A. Noce, G. Splendiani, C. Cortese, G. Federici, and M. Dessi' Effects of Folic Acid Before and After Vitamin B12 on Plasma Homocysteine Concentrations in Hemodialysis Patients with Known MTHFR Genotypes Clin. Chem., January 1, 2006; 52(1): 145 - 148. [Abstract] [Full Text] [PDF]

				R. Fux, D. Kloor, M. Hermes, T. Rock, B. Proksch, A. Grenz, U. Delabar, R. Bucheler, S. Igel, K. Morike, et al. Effect of acute hyperhomocysteinemia on methylation potential of erythrocytes and on DNA methylation of lymphocytes in healthy male volunteers Am J Physiol Renal Physiol, October 1, 2005; 289(4): F786 - F792. [Abstract] [Full Text] [PDF]

				S. E Chiuve, E. L Giovannucci, S. E Hankinson, D. J Hunter, M. J Stampfer, W. C Willett, and E. B Rimm Alcohol intake and methylenetetrahydrofolate reductase polymorphism modify the relation of folate intake to plasma homocysteine Am. J. Clinical Nutrition, July 1, 2005; 82(1): 155 - 162. [Abstract] [Full Text] [PDF]

				K. M von Castel-Dunwoody, G. P. Kauwell, K. P Shelnutt, J. D Vaughn, E. R Griffin, D. R Maneval, D. W Theriaque, and L. B Bailey Transcobalamin 776C->G polymorphism negatively affects vitamin B-12 metabolism Am. J. Clinical Nutrition, June 1, 2005; 81(6): 1436 - 1441. [Abstract] [Full Text] [PDF]

				J-L Gueant, G Anello, P Bosco, R-M Gueant-Rodriguez, A Romano, C Barone, P Gerard, and C Romano Homocysteine and related genetic polymorphisms in Down's syndrome IQ J. Neurol. Neurosurg. Psychiatry, May 1, 2005; 76(5): 706 - 709. [Abstract] [Full Text] [PDF]

				J. Frederiksen, K. Juul, P. Grande, G. B. Jensen, T. V. Schroeder, A. Tybjaerg-Hansen, and B. G. Nordestgaard Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: prospective and case-control studies from the Copenhagen City Heart Study Blood, November 15, 2004; 104(10): 3046 - 3051. [Abstract] [Full Text] [PDF]

				B. Smolkova, M. Dusinska, K. Raslova, M. Barancokova, A. Kazimirova, A. Horska, V. Spustova, and A. Collins Folate levels determine effect of antioxidant supplementation on micronuclei in subjects with cardiovascular risk Mutagenesis, November 1, 2004; 19(6): 469 - 476. [Abstract] [Full Text] [PDF]

				G. V Dedoussis, D. B Panagiotakos, C. Chrysohoou, C. Pitsavos, A. Zampelas, D. Choumerianou, and C. Stefanadis Effect of interaction between adherence to a Mediterranean diet and the methylenetetrahydrofolate reductase 677C->T mutation on homocysteine concentrations in healthy adults: the ATTICA Study Am. J. Clinical Nutrition, October 1, 2004; 80(4): 849 - 854. [Abstract] [Full Text] [PDF]

				M. Terzolo, B. Allasino, S. Bosio, E. Brusa, F. Daffara, M. Ventura, E. Aroasio, G. Sacchetto, G. Reimondo, A. Angeli, et al. Hyperhomocysteinemia in Patients with Cushing's Syndrome J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3745 - 3751. [Abstract] [Full Text] [PDF]

				E. M. Wrone, J. M. Hornberger, J. L. Zehnder, L. M. McCann, N. S. Coplon, and S. P. Fortmann Randomized Trial of Folic Acid for Prevention of Cardiovascular Events in End-Stage Renal Disease J. Am. Soc. Nephrol., February 1, 2004; 15(2): 420 - 426. [Abstract] [Full Text] [PDF]

				B. Voetsch and J. Loscalzo Genetic Determinants of Arterial Thrombosis Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 216 - 229. [Abstract] [Full Text]

				H. Refsum, A. D. Smith, P. M. Ueland, E. Nexo, R. Clarke, J. McPartlin, C. Johnston, F. Engbaek, J. Schneede, C. McPartlin, et al. Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion Clin. Chem., January 1, 2004; 50(1): 3 - 32. [Abstract] [Full Text] [PDF]

				K. He, A. Merchant, E. B. Rimm, B. A. Rosner, M. J. Stampfer, W. C. Willett, and A. Ascherio Folate, Vitamin B6, and B12 Intakes in Relation to Risk of Stroke Among Men Stroke, January 1, 2004; 35(1): 169 - 174. [Abstract] [Full Text] [PDF]

				K. P. Shelnutt, G. P. A. Kauwell, C. M. Chapman, J. F. Gregory III, D. R. Maneval, A. A. Browdy, D. W. Theriaque, and L. B. Bailey Folate Status Response to Controlled Folate Intake Is Affected by the Methylenetetrahydrofolate Reductase 677C->T Polymorphism in Young Women J. Nutr., December 1, 2003; 133(12): 4107 - 4111. [Abstract] [Full Text] [PDF]

				L. D. Spotila, P. F. Jacques, P. B. Berger, K. V. Ballman, R. C. Ellison, and R. Rozen Age Dependence of the Influence of Methylenetetrahydrofolate Reductase Genotype on Plasma Homocysteine Level Am. J. Epidemiol., November 1, 2003; 158(9): 871 - 877. [Abstract] [Full Text] [PDF]

				G. T. Russo, S. Friso, P. F. Jacques, G. Rogers, D. Cucinotta, P. W. F. Wilson, J. M. Ordovas, I. H. Rosenberg, and J. Selhub Age and Gender Affect the Relation between Methylenetetrahydrofolate Reductase C677T Genotype and Fasting Plasma Homocysteine Concentrations in the Framingham Offspring Study Cohort J. Nutr., November 1, 2003; 133(11): 3416 - 3421. [Abstract] [Full Text] [PDF]

				E. Giovannucci, J. Chen, S. A. Smith-Warner, E. B. Rimm, C. S. Fuchs, C. Palomeque, W. C. Willett, and D. J. Hunter Methylenetetrahydrofolate Reductase, Alcohol Dehydrogenase, Diet, and Risk of Colorectal Adenomas Cancer Epidemiol. Biomarkers Prev., October 1, 2003; 12(10): 970 - 979. [Abstract] [Full Text] [PDF]

				Z. Li, L. Sun, H. Zhang, Y. Liao, D. Wang, B. Zhao, Z. Zhu, J. Zhao, A. Ma, Y. Han, et al. Elevated Plasma Homocysteine Was Associated With Hemorrhagic and Ischemic Stroke, but Methylenetetrahydrofolate Reductase Gene C677T Polymorphism Was a Risk Factor for Thrombotic Stroke: A Multicenter Case-Control Study in China Stroke, September 1, 2003; 34(9): 2085 - 2090. [Abstract] [Full Text] [PDF]

				S. Kishi, J. Griener, C. Cheng, S. Das, E. H. Cook, D. Pei, M. Hudson, J. Rubnitz, J. T. Sandlund, C.-H. Pui, et al. Homocysteine, Pharmacogenetics, and Neurotoxicity in Children With Leukemia J. Clin. Oncol., August 15, 2003; 21(16): 3084 - 3091. [Abstract] [Full Text] [PDF]

				D. Girelli, N. Martinelli, F. Pizzolo, S. Friso, O. Olivieri, C. Stranieri, E. Trabetti, G. Faccini, E. Tinazzi, P. F. Pignatti, et al. The Interaction between MTHFR 677 C->T Genotype and Folate Status Is a Determinant of Coronary Atherosclerosis Risk J. Nutr., May 1, 2003; 133(5): 1281 - 1285. [Abstract] [Full Text] [PDF]

				K. Kohara, M. Fujisawa, F. Ando, Y. Tabara, N. Niino, T. Miki, and H. Shimokata MTHFR Gene Polymorphism as a Risk Factor for Silent Brain Infarcts and White Matter Lesions in the Japanese General Population: The NILS-LSA Study Stroke, May 1, 2003; 34(5): 1130 - 1135. [Abstract] [Full Text] [PDF]

				R. Castro, I. Rivera, P. Ravasco, C. Jakobs, H.J. Blom, M.E. Camilo, and I.T. de Almeida 5,10-Methylenetetrahydrofolate reductase 677C->T and 1298A->C mutations are genetic determinants of elevated homocysteine QJM, April 1, 2003; 96(4): 297 - 303. [Abstract] [Full Text] [PDF]

				K. Robien and C. M. Ulrich 5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Leukemia Risk: A HuGE Minireview Am. J. Epidemiol., April 1, 2003; 157(7): 571 - 582. [Abstract] [Full Text] [PDF]

				B. T. Heijmans, J. M. A. Boer, H. E. D. Suchiman, C. J. Cornelisse, R. G. J. Westendorp, D. Kromhout, E. J. M. Feskens, and P. E. Slagboom A Common Variant of the Methylenetetrahydrofolate Reductase Gene (1p36) Is Associated with an Increased Risk of Cancer Cancer Res., March 15, 2003; 63(6): 1249 - 1253. [Abstract] [Full Text] [PDF]

				A. de Bree, W. M. Verschuren, A.-L. Bjorke-Monsen, N. M. van der Put, S. G Heil, F. J. Trijbels, and H. J Blom Effect of the methylenetetrahydrofolate reductase 677C->T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample Am. J. Clinical Nutrition, March 1, 2003; 77(3): 687 - 693. [Abstract] [Full Text] [PDF]

				U. B. Fallon, Y. Ben-Shlomo, P.J. Kelly, J. Rosand, V. Shih, J. Kistler, and K.L. Furie Homocysteine, MTHFR 677C->T polymorphism, and risk of ischemic stroke: Results of a meta-analysis Neurology, February 11, 2003; 60(3): 526 - 527. [Full Text] [PDF]

				F. Orio Jr., S. Palomba, S. Di Biase, A. Colao, L. Tauchmanova, S. Savastano, D. Labella, T. Russo, F. Zullo, and G. Lombardi Homocysteine Levels and C677T Polymorphism of Methylenetetrahydrofolate Reductase in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 673 - 679. [Abstract] [Full Text] [PDF]

				G. Davey Smith and S. Ebrahim 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int. J. Epidemiol., February 1, 2003; 32(1): 1 - 22. [Abstract] [Full Text] [PDF]

				G. C. Rampersaud, G. P.A. Kauwell, and L. B. Bailey Folate: A Key to Optimizing Health and Reducing Disease Risk in the Elderly J. Am. Coll. Nutr., February 1, 2003; 22(1): 1 - 8. [Abstract] [Full Text] [PDF]

				S. J. Moat, P. A.L. Ashfield-Watt, H. J. Powers, R. G. Newcombe, and I. F.W. McDowell Effect of Riboflavin Status on the Homocysteine-lowering Effect of Folate in Relation to the MTHFR (C677T) Genotype Clin. Chem., February 1, 2003; 49(2): 295 - 302. [Abstract] [Full Text] [PDF]

				R. Meleady, P. M Ueland, H. Blom, A. S Whitehead, H. Refsum, L. E Daly, S. E. Vollset, C. Donohue, B. Giesendorf, I. M Graham, et al. Thermolabile methylenetetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: the European Concerted Action Project Am. J. Clinical Nutrition, January 1, 2003; 77(1): 63 - 70. [Abstract] [Full Text] [PDF]

				W. L. Carroll, D. Bhojwani, D.-J. Min, E. Raetz, M. Relling, S. Davies, J. R. Downing, C. L. Willman, and J. C. Reed Pediatric Acute Lymphoblastic Leukemia Hematology, January 1, 2003; 2003(1): 102 - 131. [Abstract] [Full Text] [PDF]

				A. De Bree, W. M. M. Verschuren, D. Kromhout, L. A. J. Kluijtmans, and H. J. Blom Homocysteine Determinants and the Evidence to What Extent Homocysteine Determines the Risk of Coronary Heart Disease Pharmacol. Rev., December 1, 2002; 54(4): 599 - 618. [Abstract] [Full Text] [PDF]

				A. De Bree, W. M. Verschuren, D. Kromhout, L. I Mennen, H. J Blom, E. S Ford, S J. Smith, D. F Stroup, K. K Steinberg, P. W Mueller, et al. Homocysteine and coronary heart disease: the importance of a distinction between low and high risk subjects Int. J. Epidemiol., December 1, 2002; 31(6): 1268 - 1272. [Full Text] [PDF]

				H. Austin, M. I. Chimowitz, H. A. Hill, S. Chaturvedi, L. R. Wechsler, R. J. Wityk, E. Walz, J. L. Wilterdink, B. Coull, C. A. Sila, et al. Cryptogenic Stroke in Relation to Genetic Variation in Clotting Factors and Other Genetic Polymorphisms Among Young Men and Women * Editorial Comment Stroke, December 1, 2002; 33(12): 2762 - 2768. [Abstract] [Full Text] [PDF]

				D. S Wald, M. Law, and J. K Morris Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis BMJ, November 23, 2002; 325(7374): 1202 - 1206. [Abstract] [Full Text] [PDF]

				M. Klerk, P. Verhoef, R. Clarke, H. J. Blom, F. J. Kok, E. G. Schouten, and and the MTHFR Studies Collaboration Group MTHFR 677C->T Polymorphism and Risk of Coronary Heart Disease: A Meta-analysis JAMA, October 23, 2002; 288(16): 2023 - 2031. [Abstract] [Full Text] [PDF]

				P. J. Kelly, J. Rosand, J. P. Kistler, V. E. Shih, S. Silveira, A. Plomaritoglou, and K. L. Furie Homocysteine, MTHFR 677C->T polymorphism, and risk of ischemic stroke: Results of a meta-analysis Neurology, August 27, 2002; 59(4): 529 - 536. [Abstract] [Full Text] [PDF]

				H. McNulty, M. C McKinley, B. Wilson, J. McPartlin, J. Strain, D. G Weir, and J. M Scott Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements Am. J. Clinical Nutrition, August 1, 2002; 76(2): 436 - 441. [Abstract] [Full Text] [PDF]

				P. A. Ashfield-Watt, C. H Pullin, J. M Whiting, Z. E Clark, S. J Moat, R. G Newcombe, M. L Burr, M. J Lewis, H. J Powers, and I. F. McDowell Methylenetetrahydrofolate reductase 677C->T genotype modulates homocysteine responses to a folate-rich diet or a low-dose folic acid supplement: a randomized controlled trial Am. J. Clinical Nutrition, July 1, 2002; 76(1): 180 - 186. [Abstract] [Full Text] [PDF]

				J.D. Kark, R. Sinnreich, I.H. Rosenberg, P.F. Jacques, and J. Selhub Plasma Homocysteine and Parental Myocardial Infarction in Young Adults in Jerusalem Circulation, June 11, 2002; 105(23): 2725 - 2729. [Abstract] [Full Text] [PDF]

				P.J. Kelly, M. Barron, K.L. Furie, P. Madonna, A. Coppola, and A. M. Cerbone Hyperhomocysteinemia, MTHFR 677C->T Polymorphism, and Stroke * Response: Stroke, June 1, 2002; 33(6): 1452 - 1453. [Full Text] [PDF]

				A. E. van Ede, R. F. J. M. Laan, H. J. Blom, G. H. J. Boers, C. J. Haagsma, C. M. G. Thomas, T. M. de Boo, and L. B. A. van de Putte Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis Rheumatology, June 1, 2002; 41(6): 658 - 665. [Abstract] [Full Text] [PDF]

				G. Schnyder, M. Roffi, Y. Flammer, R. Pin, and O.M. Hess Association of plasma homocysteine with restenosis after percutaneous coronary angioplasty Eur. Heart J., May 1, 2002; 23(9): 726 - 733. [Abstract] [Full Text] [PDF]

				B. N Ames, I. Elson-Schwab, and E. A Silver High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km): relevance to genetic disease and polymorphisms Am. J. Clinical Nutrition, April 1, 2002; 75(4): 616 - 658. [Abstract] [Full Text] [PDF]

				M. A Vickers, F. R Green, C. Terry, B. M Mayosi, C. Julier, M. Lathrop, P. J Ratcliffe, H. C Watkins, and B. Keavney Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein Cardiovasc Res, March 1, 2002; 53(4): 1029 - 1034. [Abstract] [Full Text] [PDF]

				K. R Dimitrova, K. DeGroot, A. K Myers, and Y. D Kim Estrogen and homocysteine Cardiovasc Res, February 15, 2002; 53(3): 577 - 588. [Abstract] [Full Text] [PDF]

				I. P Fohr, R. Prinz-Langenohl, A. Bronstrup, A. M Bohlmann, H. Nau, H. K Berthold, and K. Pietrzik 5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women Am. J. Clinical Nutrition, February 1, 2002; 75(2): 275 - 282. [Abstract] [Full Text] [PDF]

				M.C. Verhaar, E. Stroes, and T.J. Rabelink Folates and Cardiovascular Disease Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 6 - 13. [Abstract] [Full Text] [PDF]

				R. Butler, A. D. Morris, and A. D. Struthers The T Allele of The C677T 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism May Protect Endothelial Function in Young, Normal Subjects Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 193 - 194. [Full Text] [PDF]

				P. Madonna, V. de Stefano, A. Coppola, F. Cirillo, A. M. Cerbone, G. Orefice, and G. Di Minno Hyperhomocysteinemia and Other Inherited Prothrombotic Conditions in Young Adults With a History of Ischemic Stroke Stroke, January 1, 2002; 33(1): 51 - 56. [Abstract] [Full Text] [PDF]

				C. H. Pullin, P. A. L. Ashfield-Watt, M. L. Burr, Z. E. Clark, M. J. Lewis, S. J. Moat, R. G. Newcombe, H. J. Powers, J. M. Whiting, and I. F. W. McDowell Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1799 - 1805. [Abstract] [Full Text] [PDF]

				G. Schnyder, M. Roffi, R. Pin, Y. Flammer, H. Lange, F. R. Eberli, B. Meier, Z. G. Turi, and O. M. Hess Decreased Rate of Coronary Restenosis after Lowering of Plasma Homocysteine Levels N. Engl. J. Med., November 29, 2001; 345(22): 1593 - 1600. [Abstract] [Full Text] [PDF]

				H. Markus, Z. Kapozsta, R. Ditrich, C. Wolfe, N. Ali, J. Powell, M. Mendell, and M. Cullinane Increased Common Carotid Intima-Media Thickness in UK African Caribbeans and Its Relation to Chronic Inflammation and Vascular Candidate Gene Polymorphisms Stroke, November 1, 2001; 32(11): 2465 - 2471. [Abstract] [Full Text] [PDF]

				S. Lopaciuk, K. Bykowska, H. Kwiecinski, A. Mickielewicz, A. Czlcankawska, T. Mendel, A. Kuczynska-Zardzewialy, D. Szelagowska, J. Windyga, W. Schroder, et al. Factor V Leiden, Prothrombin Gene G20210A Variant, and Methylenetetrahydrofolate Reductase C677T Genotype in Young Adults With Ischemic Stroke Clinical and Applied Thrombosis/Hemostasis, October 1, 2001; 7(4): 346 - 350. [Abstract] [PDF]

				J. Thambyrajah, M. J. Landray, H. J. Jones, F. J. McGlynn, D. C. Wheeler, and J. N. Townend A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1858 - 1863. [Abstract] [Full Text] [PDF]

				M. S. Williams and P. F. Bray Genetics of Arterial Prothrombotic Risk States Experimental Biology and Medicine, May 1, 2001; 226(5): 409 - 419. [Abstract] [Full Text]

				C. Song, D. Xing, W. Tan, Q. Wei, and D. Lin Methylenetetrahydrofolate Reductase Polymorphisms Increase Risk of Esophageal Squamous Cell Carcinoma in a Chinese Population Cancer Res., April 1, 2001; 61(8): 3272 - 3275. [Abstract] [Full Text]

				M. Roest, Y. T. van der Schouw, D. E. Grobbee, M. J. Tempelman, P. G. de Groot, J. J. Sixma, and J. D. Banga Methylenetetrahydrofolate Reductase 677 C/T Genotype and Cardiovascular Disease Mortality in Postmenopausal Women Am. J. Epidemiol., April 1, 2001; 153(7): 673 - 679. [Abstract] [Full Text] [PDF]

				B. Keavney and H. Watkins Evolution of genetic analysis strategies in coronary heart disease: a case of unnatural selection? Eur. Heart J., February 2, 2001; 22(4): 271 - 273. [PDF]

				L.A.J Kluijtmans and A.S Whitehead Methylenetetrahydrofolate reductase genotypes and predisposition to atherothrombotic disease. Evidence that all three MTHFR C677T genotypes confer different levels of risk Eur. Heart J., February 2, 2001; 22(4): 294 - 299. [Abstract] [PDF]

				S.-M. Saw, J.-M. Yuan, C.-N. Ong, K. Arakawa, H.-P. Lee, G. A Coetzee, and M. C Yu Genetic, dietary, and other lifestyle determinants of plasma homocysteine concentrations in middle-aged and older Chinese men and women in Singapore Am. J. Clinical Nutrition, February 1, 2001; 73(2): 232 - 239. [Abstract] [Full Text] [PDF]

				D. J. Meiklejohn, M. A. Vickers, R. Dijkhuisen, and M. Greaves Plasma Homocysteine Concentrations in the Acute and Convalescent Periods of Atherothrombotic Stroke Stroke, January 1, 2001; 32(1): 57 - 62. [Abstract] [Full Text] [PDF]

				E. E Delvin, R. Rozen, A. Merouani, J. Genest Jr, and M. Lambert Influence of methylenetetrahydrofolate reductase genotype, age, vitamin B-12, and folate status on plasma homocysteine in children Am. J. Clinical Nutrition, December 1, 2000; 72(6): 1469 - 1473. [Abstract] [Full Text] [PDF]

				J. C. Chambers, H. Ireland, E. Thompson, P. Reilly, O. A. Obeid, H. Refsum, P. Ueland, D. A. Lane, and J. S. Kooner Methylenetetrahydrofolate Reductase 677 C->T Mutation and Coronary Heart Disease Risk in UK Indian Asians Arterioscler Thromb Vasc Biol, November 1, 2000; 20(11): 2448 - 2452. [Abstract] [Full Text] [PDF]

				A. Hassan and H. S. Markus Genetics and ischaemic stroke Brain, September 1, 2000; 123(9): 1784 - 1812. [Abstract] [Full Text] [PDF]

				L. L. Stern, J. B. Mason, J. Selhub, and S.-W. Choi Genomic DNA Hypomethylation, a Characteristic of Most Cancers, Is Present in Peripheral Leukocytes of Individuals Who Are Homozygous for the C677T Polymorphism in the Methylenetetrahydrofolate Reductase Gene Cancer Epidemiol. Biomarkers Prev., August 1, 2000; 9(8): 849 - 853. [Abstract] [Full Text]

				L. Brattstrom and D. E. Wilcken Homocysteine and cardiovascular disease: cause or effect? Am. J. Clinical Nutrition, August 1, 2000; 72(2): 315 - 323. [Abstract] [Full Text] [PDF]

				P. M Ueland, H. Refsum, S. A. Beresford, and S. E. Vollset The controversy over homocysteine and cardiovascular risk Am. J. Clinical Nutrition, August 1, 2000; 72(2): 324 - 332. [Abstract] [Full Text] [PDF]

				S. Hustad, P. M. Ueland, S. E. Vollset, Y. Zhang, A. L. Bjorke-Monsen, and J. Schneede Riboflavin as a Determinant of Plasma Total Homocysteine: Effect Modification by the Methylenetetrahydrofolate Reductase C677T Polymorphism Clin. Chem., August 1, 2000; 46(8): 1065 - 1071. [Abstract] [Full Text] [PDF]

				G. L. Booth, E. E.L. Wang, and with the Canadian Task Force on Preventive Health Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events Can. Med. Assoc. J., July 1, 2000; 163(1): 21 - 29. [Abstract] [Full Text] [PDF]

				H. KIMURA, F. GEJYO, S. SUZUKI, and R. MIYAZAKI The C677T Methylenetetrahydrofolate Reductase Gene Mutation in Hemodialysis Patients J. Am. Soc. Nephrol., May 1, 2000; 11(5): 885 - 893. [Abstract] [Full Text]

				J. W. Eikelboom, G. J. Hankey, S. S. Anand, E. Lofthouse, N. Staples, and R. I. Baker Association Between High Homocyst(e)ine and Ischemic Stroke due to Large- and Small-Artery Disease but Not Other Etiologic Subtypes of Ischemic Stroke Stroke, May 1, 2000; 31(5): 1069 - 1075. [Abstract] [Full Text] [PDF]

				D. H. J. Blom and D. P. Verhoef Hyperhomocysteinemia, MTHFR, and Risk of Vascular Disease Circulation, April 25, 2000; 101 (16): e171 - e171. [Full Text] [PDF]

				A. Mager, P. Tiqva, D. L. Brattstrom, L. Brudin, P. D. E.L. Wilcken, and J. Ohrvik Methylenetetrahydrofolate Reductase Gene and Coronary Artery Disease Response Circulation, April 25, 2000; 101 (16): e172 - e173. [Full Text] [PDF]

				M. A. Mansoor, C. Bergmark, S. J. Haswell, I. F. Savage, P. H. Evans, R. K. Berge, A. M. Svardal, and O. Kristensen Correlation between Plasma Total Homocysteine and Copper in Patients with Peripheral Vascular Disease Clin. Chem., March 1, 2000; 46(3): 385 - 391. [Abstract] [Full Text] [PDF]

				S. E. Vollset, O. Nygard, H. Refsum, and P. M. Ueland Coffee and homocysteine1 Am. J. Clinical Nutrition, February 1, 2000; 71(2): 403 - 404. [Full Text] [PDF]

				K. ROBINSON Homocysteine, B vitamins, and risk of cardiovascular disease Heart, February 1, 2000; 83(2): 127 - 130. [Full Text]

				B. N. Ames Cancer prevention and diet: Help from single nucleotide polymorphisms PNAS, October 26, 1999; 96(22): 12216 - 12218. [Full Text] [PDF]

				J. D. Kark, J. Selhub, B. Adler, J. Gofin, J. H. Abramson, G. Friedman, and I. H. Rosenberg Nonfasting Plasma Total Homocysteine Level and Mortality in Middle-Aged and Elderly Men and Women in Jerusalem Ann Intern Med, September 7, 1999; 131(5): 321 - 330. [Abstract] [Full Text] [PDF]

				A. G. Bostom, I. H. Rosenberg, H. Silbershatz, P. F. Jacques, J. Selhub, R. B. D'Agostino, P. W.F. Wilson, and P. A. Wolf Nonfasting Plasma Total Homocysteine Levels and Stroke Incidence in Elderly Persons: The Framingham Study Ann Intern Med, September 7, 1999; 131(5): 352 - 355. [Abstract] [Full Text] [PDF]

				J. W. Eikelboom, E. Lonn, J. Genest Jr., G. Hankey, and S. Yusuf Homocyst(e)ine and Cardiovascular Disease: A Critical Review of the Epidemiologic Evidence Ann Intern Med, September 7, 1999; 131(5): 363 - 375. [Abstract] [Full Text] [PDF]

				S. N. Doshi, J. Goodfellow, M. J. Lewis, and I. F.W. McDowell Homocysteine and endothelial function Cardiovasc Res, June 1, 1999; 42(3): 578 - 582. [Full Text] [PDF]

				P. M. Ridker, J. E. Manson, J. E. Buring, J. Shih, M. Matias, and C. H. Hennekens Homocysteine and Risk of Cardiovascular Disease Among Postmenopausal Women JAMA, May 19, 1999; 281(19): 1817 - 1821. [Abstract] [Full Text] [PDF]

				A. G. Bostom and J. Selhub Homocysteine and Arteriosclerosis : Subclinical and Clinical Disease Associations Circulation, May 11, 1999; 99(18): 2361 - 2363. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brattström, L. Articles by Brudin, L. Search for Related Content PubMed PubMed Citation Articles by Brattström, L. Articles by Brudin, L.