AJCN EB Program 2010
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Brattström, L.
Right arrow Articles by Wilcken, D. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brattström, L.
Right arrow Articles by Wilcken, D. E.
Agricola
Right arrow Articles by Brattström, L.
Right arrow Articles by Wilcken, D. E.
American Journal of Clinical Nutrition, Vol. 72, No. 2, 315-323, August 2000
© 2000 American Society for Clinical Nutrition

Perspectives

Homocysteine and cardiovascular disease: cause or effect?1,2

Lars Brattström and David EL Wilcken

1 From the Department of Medicine, County Hospital, Kalmar, Sweden, and the Department of Cardiovascular Medicine, University of New South Wales, The Prince of Wales Hospital, Sydney, Australia.

2 Address reprint requests to L Brattström, Department of Medicine, County Hospital, S-391 85 Kalmar, Sweden. E-mail: lars.brattstrom{at}ltkalmar.se.

ABSTRACT

Both markedly and mildly elevated circulating homocysteine concentrations are associated with increased risk of vascular occlusion. Here we review possible mechanisms that mediate these effects. Inborn errors of homocysteine metabolism result in markedly elevated plasma homocysteine (200–300 µmol/L) and thromboembolic (mainly venous) disease: treatment to lower but not to normalize these concentrations prevents vascular events. Mild homocysteine elevation (>15 µmol/L) occurs in {approx}20–30% of patients with atherosclerotic disease. Usually, this is easily normalized with oral folate and ongoing trials are assessing the effect of folate treatment on outcomes. Although there is evidence of endothelial dysfunction with both markedly and mildly elevated homocysteine concentrations, the elevated homocysteine concentration in atherosclerotic patients is also associated with most standard vascular risk factors, and importantly, with early decline in renal function, which is common in atherosclerosis. Decline in renal function alone causes elevated plasma homocysteine (and cysteine). These observations suggest that mild hyperhomocysteinemia could often be an effect rather than a cause of atherosclerotic disease. Data on the common C677T methylenetetrahydrofolate reductase polymorphism supports this, in that, although homozygosity is a frequent cause of mild hyperhomocysteinemia when plasma folate is below median population concentrations, it appears not to increase cardiovascular risk. Indeed, there is recent evidence suggesting an acute antioxidant effect of folic acid independent of its effect on homocysteine concentrations. This antioxidant mechanism may oppose an oxidant effect of homocysteine and be relevant to treatment of patients with vascular disease, especially those with chronic renal insufficiency. Such patients have moderately elevated plasma homocysteine and greatly increased cardiovascular risk that is largely unexplained.

Key Words: Homocysteine • cardiovascular disease • methylenetetrahydrofolate reductase • folic acid • oxidative stress • thromboembolism • renal function

INTRODUCTION

Despite the impressive epidemiologic evidence that mild hyperhomocysteinemia is an independent risk factor for atherosclerotic and atherothrombotic vascular disease, we have become increasingly doubtful as to whether modest elevations of plasma homocysteine may be causally involved in the pathogenesis of atherosclerosis. As will be outlined in this review, there are now substantial indications that a modest elevation of plasma homocysteine is usually benign and is a consequence rather than a cause of atherosclerosis.

A REVIEW OF THE EVIDENCE

Homocystinuria and vascular disease
First, it must be emphasized that the vascular disease in homocystinuria due to cystathionine ß-synthase (CBS) deficiency, methylenetetrahydrofolate reductase (MTHFR) deficiency, or inborn errors in cobalamin metabolism bears little resemblance to the atherosclerotic and atherothrombotic vascular disease seen in the adult general population. Atherosclerosis is characterized by a thickening of the arterial wall due to smooth muscle cell proliferation, lipid deposits, and fibrosis (1). Rupture of the lipid-containing atherosclerotic plaques results in thrombosis (atherothrombosis) and leads to myocardial infarction and stroke (1). In contrast, homocystinuria seems to be associated with a primary thrombotic disorder that affects veins more often than arteries (2). Stroke in homocystinuric patients is frequently due to intracranial venous thrombosis, which is a rare cause of stroke in the general population (3–10). Multifocal old and fresh mural thromboses in different stages of organization are found postmortem (7, 8, 11–15). The changes in the arterial wall are patchy, lack lipid deposits in young patients and have an appearance that may represent the arterial wall repair response to repeated mural thrombosis (8, 11, 15–17). Therefore, homocystinuria seems to be associated with a factor or factors that primarily cause venous and arterial thrombosis. Whether the same factor (that in homocystinuria does not seem to cause the characteristic changes of primary atherosclerosis) would be atherogenic in much lower concentrations in the general population remains uncertain.

In 1969, McCully (18) put forward the homocysteine theory of arteriosclerosis. This was based on the findings of arterial changes in an infant with homocystinuria due to CBS deficiency similar to those in an infant with homocystinuria due to a remethylation defect, one an inborn error involving the transsulfuration pathway (CBS deficiency) and the other an inborn error affecting the remethylation of homocysteine to methionine. The changes in the arterial wall lacked lipid deposits and were classified as arteriosclerosis (not atherosclerosis) (18). Because the 2 different disorders shared markedly elevated homocysteine concentrations as a metabolic consequence of the inborn errors but with widely different concentrations of methionine, homocysteine or a derivative of homocysteine was considered to be the common factor leading to arterial damage (18).

In homocystinuria, there is evidence that the very high homocysteine concentrations are thrombogenic. However, in both CBS deficiency and inborn errors of homocysteine remethylation, the precursor of homocysteine, S-adenosylhomocysteine (SAH), will most likely also accumulate. SAH is the demethylated product of numerous S-adenosylmethionine (SAM)-dependent transmethylation reactions and a potent feedback inhibitor of the same reactions (19). It is possible that SAH accumulation leads to hypomethylation of some essential components (19), the tissue-specific sensitivity of which may explain both similarities (thrombosis) and dissimilarities (ectopia lentis, skeletal deformities, and osteoporosis) between the 2 forms of homocystinuria (ie, that due to CBS deficiency or that due remethylation defects). In homocystinuria, therapy that lowers plasma homocysteine concentration also reduces SAH and restores impaired transmethylation reactions. In patients with CBS deficiency, this has been shown to effectively reduce the risk of thrombotic events, although plasma homocysteine concentrations frequently remain well above normal values (20–22). This suggests that the threshold of homocysteine concentration for thrombogenesis is clearly higher than the modestly elevated concentrations of homocysteine found in patients with cardiovascular disease.

Mild hyperhomocysteinemia and vascular disease
The important core question is: does a modest elevation of plasma homocysteine concentration (eg, from 15 to 20 µmol/L) contribute to the pathogenesis of atherosclerotic vascular disease, or is it merely a marker for increased risk? Several studies established that the association between plasma homocysteine concentration and the risk of cardiovascular disease or severity of atherosclerosis is graded throughout the normal range from low to mildly elevated concentrations (23, 24). If this graded relation reflects a pathogenic role of homocysteine in the development of cardiovascular disease, one could assume that any cause of longstanding, mild hyperhomocysteinemia would also be associated with increased cardiovascular risk. Well-known, common causes of hyperhomocysteinemia are low serum or red cell folate concentrations (25, 26), vitamin B-12 deficiency (26, 27), decline in renal function (28, 29), and the TT genotype for the common C677T/MTHFR polymorphism in conjunction with low folate status (30). Moreover, heterozygosity for CBS deficiency is associated with normal or mild elevation of basal homocysteine concentration and frequently with an abnormal response to methionine loading with increased postload hyperhomocysteinemia (31–33).

The clinical symptoms of untreated vitamin B-12 and folate deficiency are well-known. However, whereas hyperhomocysteinemia in these conditions may be moderate (>30 µmol/L) or even severe (>100 µmol/L) (26), vascular disease is not a known complication of folate or vitamin B-12 deficiency. Folate status (serum or red cell folate or folate intake) is considered to be one of the most important determinants of plasma homocysteine concentration, and folic acid supplementation decreases plasma homocysteine concentration in almost all subjects (34–37). Much of the relation between folate status and plasma homocysteine concentration seems to be dependent on the genotype of the C677T/MTHFR polymorphism (30). There are several ongoing, randomized, blinded intervention studies with folic acid or placebo treatment of patients with vascular disease to determine whether homocysteine-lowering therapy reduces cardiovascular risk and improves outcome (38).

There were a few longitudinal studies in which homocysteine was not measured that assessed cardiovascular outcome related to folate status, with varying results (39–44). In addition, there were many studies in which both plasma homocysteine and folate status were assessed. Only one of these studies showed that a low folate status together with elevated homocysteine may constitute a risk factor for cardiovascular disease (45). Paradoxically, this small retrospective study and another prospective study showed increased incidence or risk of mortality and coronary heart disease in subjects with elevated serum vitamin B-12 concentrations (43, 45). A few other studies indicated that a poor folate status itself may be associated with increased risk but that this risk is only marginally (46–48) or only partially (49, 50) mediated by homocysteine. Although the bulk of studies confirmed the strong negative relation between folate status and plasma homocysteine concentration on one hand and the relation between increased homocysteine concentrations and cardiovascular disease on the other, the results of these studies do not suggest that the former relation is coupled to the latter. In other words, elevation of plasma homocysteine concentrations due to poor folate status seems to be benign with regard to risk or severity of cardiovascular disease (51–68). It follows from this that if ongoing intervention studies were to show that folic acid therapy reduces cardiovascular risk, an additional question would be whether the risk reduction was due to lowering of homocysteine or to some other effect of the vitamin. Recently, a prospective study in women showed that an elevated plasma homocysteine concentration predicts myocardial infarction and stroke. Self-reported multivitamin supplement use at baseline was associated with markedly lower concentrations of homocysteine but not with a lower risk of myocardial infarction or stroke during follow-up compared with nonusers (69).

The C677T/MTHFR polymorphism, homocysteine, and vascular disease
A common polymorphism (C677T) in MTHFR leads to thermolability of the enzyme and increased sensitivity to low folate concentrations (30). About 12% of the white population is homozygous (TT genotype) (30). Several studies established that TT homozygotes on average have {approx}3.5 µmol/L or 35% higher plasma homocysteine concentrations than do wild-type homozygotes (CC genotype) (70). Because high plasma homocysteine concentrations are confined to individuals with serum or plasma folate concentrations in the lower range, these TT homozygotes have even higher homocysteine elevations than those given above (70). The TT genotype is present in {approx}30% of individuals in the population who have plasma homocysteine concentrations >18 µmol/L; of those with homocysteine values >40 µmol/L, {approx}70% are TT homozygotes (30). Considering that the TT genotype is present from birth and that dietary habits in adults tend to be stable over many years, TT homozygotes with low folate intakes would indeed be expected to be exposed to markedly elevated plasma homocysteine concentrations for decades. Therefore, during the past few years, >40 investigations, including several thousands of cardiovascular patients and control subjects, studied whether the TT genotype is associated with increased risk or severity of arterial disease (30, 44, 62–64, 68, 70–86). Our conclusions from these studies are that the hyperhomocysteinemia associated with the TT genotype, even in the presence of low folate status (44), seems to be benign and not related to the risk or severity of cardiovascular disease.

Early in the homocysteine-cardiovascular disease era, the hypothesis studied was whether heterozygotes for CBS deficiency have increased risk of cardiovascular disease. As indicated above, obligate heterozygote parents of patients with homocystinuria have normal or only slightly increased fasting plasma homocysteine concentrations but commonly respond to oral loads of methionine with abnormally high plasma homocysteine concentrations (31–33, 51). Several studies have shown that patients with premature cardiovascular disease frequently respond abnormally to methionine loads and that postload hyperhomocysteinemia is a risk factor for cardiovascular disease (32, 33, 51, 87). However, an international survey did not show increased cardiovascular risk in obligate heterozygotes, although the study had relatively low power (2). Later, when DNA-based methods became available, it could not be confirmed that cardiovascular disease patients with abnormal responses to methionine were predominantly heterozygotes for common mutations leading to CBS deficiency (88, 89) or that such CBS mutations were more frequent in patients than in control subjects (90, 91). These findings suggest that abnormally high plasma homocysteine concentrations after methionine loading may not be related to an important degree to cardiovascular disease because heterozygotes for CBS deficiency who have such responses to methionine appear not to have elevated cardiovascular disease risk.

What, then, is the explanation for the frequent finding of mild hyperhomocysteinemia in association with atherothrombotic cardiovascular disease? The Hordaland Study, the largest population-based study of the relation between plasma homocysteine and risk factors for cardiovascular disease, provided important data relevant to this question (92). The study showed that elevated plasma homocysteine was strongly and positively related to major components known to be associated with atherogenesis and cardiovascular risk, ie, age, male sex, smoking, blood pressure, elevated total cholesterol, and lack of exercise. Many other studies in patients with cardiovascular disease and healthy control subjects showed similar associations. Importantly, plasma homocysteine seems to be related to blood pressure (59, 89, 93–97), which is a well-known major risk factor not only for atherosclerotic cardiovascular disease but also for nephrosclerosis and decline in renal function (98–101). Also, atherosclerosis is considered to contribute to the nephrosclerotic process (100–103).

Renal function and mild hyperhomocysteinemia
Serum creatinine, a marker with low sensitivity for early decline in renal function, is a strong determinant of plasma homocysteine concentration (29, 53, 104–107). Almost every study has shown a highly significant positive correlation between the concentrations of creatinine and homocysteine. In renal disease, both the creatinine and homocysteine concentrations increase, and in end-stage renal disease, plasma homocysteine concentrations may become 3–5 times higher than normal (28, 29, 108). From studies in both humans and animals, it was estimated that the kidneys account for {approx}70% of plasma clearance of homocysteine (109, 110). The importance of renal function for plasma homocysteine concentration has been shown in subjects with normal serum creatinine concentrations (105–107, 111). Mean plasma homocysteine concentrations were 4 µmol/L, or 45% higher in subjects with normal serum creatinine who had glomerular filtration rates (GFRs) in the lower range, assessed directly or with cystatin C, than in subjects with normal serum creatinine and GFRs in the upper range (105, 107). Moreover, in mutivariate analysis, GFR predicts plasma homocysteine concentration much more accurately than does serum creatinine (105–107, 111). This is consistent with serum creatinine being an insensitive indicator of early renal decline. As a consequence, controlling for serum creatinine to adjust statistically for the effect of mildly impaired renal function on circulating homocysteine does not provide an accurate assessment of the effect of mildly impaired renal function on plasma homocysteine concentrations.

It could be that the results of several important studies on homocysteine and cardiovascular disease or death would have been different if it had been possible to adjust for GFR instead of serum creatinine. In one prospective study that showed that plasma homocysteine strongly predicted cardiovascular mortality in patients with type 2 diabetes, homocysteine concentrations were related to GFR, but after adjustment for GFR and other covariates, the predictive value of homocysteine was completely eliminated (112).

We have put forward the view that impaired renal function due to hypertension and atherosclerosis is an important cause of the elevated plasma homocysteine found in vascular disease patients (30, 53). The reasons are as follows. Atherogenesis and elevation of blood pressure commonly develop silently over many years before the emergence of clinically evident vascular events. These processes also lead to nephrosclerosis and a degree of deterioration of renal function (98–103), and this is highly relevant to the plasma clearance of homocysteine (109). For these reasons, the presence of vascular disease itself may contribute to an elevation in circulating homocysteine by leading to a decline in renal function (53). This means that because of reduced renal function, patients with either occult or clinically evident cardiovascular disease and normal serum creatinine concentrations may have elevated circulating homocysteine concentrations. This could also explain the graded relation between plasma homocysteine and severity of atherosclerosis.

A recently published study by McQuillan et al (64) emphasized much of the points above. In 1111 subjects, carotid intima-medial wall thickness (IMT), an index of generalized atherosclerosis, was determined and found to be strongly and positively related to plasma homocysteine concentration. Among several factors, IMT was also related to advanced age, elevated blood pressure, and plasma creatinine. All of these are well-known to be associated with some decline in renal function. A strong relation between increased IMT and low GFR has been shown in diabetic patients (113). In contrast, in the study by McQuillan et al, although serum folate, folate intake, and the TT genotype of the C677T/MTHFR polymorphism were strong determinants of plasma homocysteine concentration, none of these factors alone or in combination was related to IMT (64).

Thus, we have reason to believe that much of the epidemiologic association found in prospective and retrospective studies and in cross-sectional studies between modestly elevated plasma homocysteine concentrations and cardiovascular risk or severity of atherosclerosis is explained by the renal mechanism outlined above (Figure 1Go). This constitutes the basis for our reverse causality hypothesis, which implies that mild hyperhomocysteinemia in association with atherosclerotic cardiovascular disease is a consequence and not a cause of the disease. Our hypothesis is also supported by the lack of consistent evidence that mild hyperhomocysteinemia due to reduced folate or vitamin B-12 status, heterozygosity for CBS deficiency, or homozygosity for the C677T/MTHFR gene polymorphism is associated with increased cardiovascular risk.



View larger version (32K):
[in this window]
[in a new window]
  		FIGURE 1. . Impaired renal function, poor folate or vitamin B-12 status, and the TT genotype of the C677T methylenetetrahydrofolate reductase polymorphism are common causes of elevated plasma homocysteine. Hypertension and atherosclerosis lead to nephrosclerosis and decline in renal function, which in turn leads to elevated plasma homocysteine. This mechanism may explain much of the association between plasma homocysteine and atherothrombotic vascular disease. Because there is no consistent evidence that elevated homocysteine due to low folate, low vitamin B-12, or the TT genotype is associated with increased risk of atherosclerotic or thromboembolic vascular disease, the role of a modest elevation in plasma homocysteine in cardiovascular disease is still unclear.

 
Mild hyperhomocysteinemia and venous thromboembolism
There is, however, considerable epidemiologic evidence that mild hyperhomocysteinemia is a risk factor for venous thromboembolic disease, as reviewed recently (114) and supported by other recent studies (115, 116). These are interesting findings because homocystinuria (severe hyperhomocysteinemia) seems to be associated primarily with thrombotic disease, which predominantly affects veins. Although on one hand the mild hyperhomocysteinemia associated with the usual form of vascular disease may be a reflection of an associated modest renal impairment, this mechanism does not explain a possible relation between mild hyperhomocysteinemia and venous thromboembolism because the latter is not usually associated with reduced renal function. Thus, it is possible that mild hyperhomocysteinemia itself may enhance the risk of both venous and arterial primary thrombogenesis.

To explore this possibility, we performed a meta-analysis of 15 published reports (68, 115, 117–130) on the common C677T/MTHFR polymorphism and venous thrombosis (Figure 2Go). The analysis included a total of 2683 patients with venous thromboembolism and 3306 control subjects. A sixteenth study was not included because of uncertainty regarding the ethnic origin of the patients and control subjects (125). Although the TT genotype is a major cause of mild hyperhomocysteinemia (70, 118), the prevalence of the TT genotype was the same in patients with venous thromboembolism (14.9%) as in control subjects (14.3%). The odds ratio (OR) after adjustment for heterogeneity between studies (30) was 1.09 (95% CI: 0.907, 1.316). Therefore, these findings do not support the hypothesis that mild hyperhomocysteinemia is causally related to primary venous or arterial thrombosis, assuming that the polymorphism is not in some way protective against it.



View larger version (20K):
[in this window]
[in a new window]
  		FIGURE 2. . Meta-analysis of 15 studies on the risk of venous thromboembolism in association with the commonly hyperhomocysteinemic TT genotype of the C677T methylenetetrahydrofolate reductase polymorphism compared with the normally normohomocysteinemic CT and CC genotypes. Odds ratio: 1.093 (95% CI: 0.907, 1.316). The analysis was adjusted for heterogeneity between studies (30).

 
Mild hyperhomocysteinemia and endothelial function
Recent data on interrelations between endothelium-dependant vasodilatation mediated by nitric oxide release and plasma homocysteine raise important issues. After the initial study by Celermajer et al (131) showing that endothelium-dependant vasodilatation is reduced in homocystinuric patients but not in their obligate heterozygote parents, several groups established that an {approx}3-fold increase in circulating homocysteine after a standard methionine load transiently reduces endothelium-dependant vasodilatation. In a careful study, Bellamy et al (132) also showed that a reduction of plasma total homocysteine from 14.9 ± 7.4 to 8.7 ± 2.5 µmol/L after 6 wk of oral folate supplementation (5 mg/d) enhanced endothelium-dependant brachial artery dilatation in 18 healthy adults. These effects may be mediated by a reduction in homocysteine-induced oxidative stress.

The recent findings of Kanani et al (133) support this possibility. They showed that oral ascorbic acid, a potent antioxidant, prevented endothelial dysfunction associated with a 2–3-fold increase in homocysteine after a standard methionine load (133). Chambers et al (134) reported similar findings. And in the coronary circulation, Schachinger et al (135) documented an inverse relation between a range of plasma homocysteine concentrations and endothelium-dependent coronary blood flow (135). There is also evidence that elevated homocysteine may be associated with enhanced oxidative stress. The findings of Bellamy et al (132) could be explained by folate itself having an antioxidant effect that opposes homocysteine-induced oxidative changes, as suggested by Verhaar and Rabelink (136), and in this way influences endothelial nitric oxide–mediated vasodilatation. The results of a study by Usui et al (137) provide support for this concept. They showed that a single, large (10 mg) oral folic acid dose reversed impaired flow-mediated dilatation after a standard methionine load without affecting the associated acute increase in homocysteine concentration (137).

The long-term implications of these observations for the pathogenesis of vascular disease are of course unknown. However, the persisting endothelial dysfunction associated with this order of homocysteine elevation seen in selected patient groups—particularly in patients with advanced renal failure and a small proportion of vascular patients—could enhance the atherogenic effects of other standard risk factors. This may be particularly relevant in chronic renal failure. Such patients are at greatly increased cardiovascular risk that is largely unexplained and, as mentioned, commonly have circulating homocysteine concentrations 3-fold higher than normal. Homocysteine-associated endothelial dysfunction could also increase vascular risk when occurring together with common prothrombotic factors. Factor V Leiden is an example of such a factor. It is common, with a prevalence of 4% in the Australian white population (138), and confers an increased risk of venous (but not arterial) thrombosis, a risk that may well be amplified when linked with endothelial dysfunction.

CONCLUSIONS

It has been established that lowering the markedly elevated circulating homocysteine concentrations found in patients with the inborn error of homocystinuria due to CBS deficiency, even to suboptimal concentrations, greatly reduces cardiovascular risk (20, 139). This finding defines a key role for grossly elevated homocysteine concentrations in the pathogenesis of vascular disease. The relevance to vascular risk of mild hyperhomocysteinemia is, however, still undetermined. The results of the many ongoing homocysteine-lowering trials with folic acid in vascular patients may certainly clarify whether folate therapy is relevant to cardiovascular risk in the general population and will provide much important information (38). However, if the trials show a positive effect of supplementation they will not of course separate the effects of oral folate supplementation from those of lowering homocysteine concentration. This might be done by comparing folic acid and betaine therapy in such patients because both lower circulating homocysteine but by different mechanisms. This would be an extremely interesting study but one that is unlikely to be done.

ACKNOWLEDGMENTS

We acknowledge Lars Brudin, head of the Department of Clinical Physiology, County Hospital, Kalmar, Sweden, for his invaluable help with the meta-analysis.

REFERENCES

  1. Davies MJ. Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995. Circulation 1996; 94:2013–20.[Free Full Text]
  2. Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985;37:1–31.[Medline]
  3. Erbe RW. Inborn errors of folate metabolism. In: Blakely RL, ed. Folates and pterins. Boston: John Wiley & Sons, Inc, 1986:413–65.
  4. Kerrin D, Murdoch Eaton D, Livingston J, Henderson M, Smith M. Homocystinuria presenting with sagittal sinus thrombosis in infancy. J Child Neurol 1996;11:70–1.[Free Full Text]
  5. Visy JM, Le Coz P, Chadefaux B, et al. Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency revealed by stroke in adult siblings. Neurology 1991;41:1313–5.[Abstract/Free Full Text]
  6. Cochran FB, Packman S. Homocystinuria presenting as sagittal sinus thrombosis. Eur Neurol 1992;32:1–3.[Medline]
  7. James TN, Carson NA, Froggatt P. De subitaneis mortibus. IV. Coronary vessels and conduction system in homocystinuria. Circulation 1974;49:367–74.[Abstract/Free Full Text]
  8. Gibson JB, Carson NAJ, Neill DW. Pathological findings in homocystinuria. J Clin Pathol 1964;17:427–37.
  9. Hopkins I, Townley RR, Shipman RT. Cerebral thrombosis in a patient with homocystinuria. J Pediatr 1969;75:1082–3.[Medline]
  10. Carson NAJ, Dent CE, Field CMB, Gaull GE. Homocystinuria. J Pediatr 1965;66:565–83.
  11. White HH, Rowland LP, Araki S, Thomson HL, Cowen D. Homocystinuria. Arch Neurol 1965;13:455–70.
  12. Dunn HG, Perry TL, Dolman CL. Homocystinuria. A recently discovered cause of mental defect and cerebrovascular thrombosis. Neurology 1966;16:407–20.[Free Full Text]
  13. Gaull G. Homocystinuria. Adv Teratol 1967;2:101–25.
  14. Carey MC, Donovan DE, FitzGerald O, McAuley FD. Homocystinuria. I. A clinical and pathological study of nine subjects in six families. Am J Med 1968;45:7–25.[Medline]
  15. McKusick VA. Homocystinuria. Heritable disorders of connective tissues. 4th ed. St Louis: CV Mosby Co, 1972:224–81.
  16. Schimke RN, McKusick VA, Huang T, Pollack AD. Homocystinuria. JAMA 1965;193:87–95.
  17. Wilcken DEL, Dudman NPB. Homocystinuria and atherosclerosis. In: Lusis RS, Rotter JI, Sparkes RS, eds. Molecular genetics of coronary artery disease. Candidate genes and processes in atherosclerosis. Basel, Switzerland: Karger, 1992:311–24.
  18. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969;56:111–28.[Medline]
  19. Langman LJ, Cole DE. Homocysteine. Crit Rev Clin Lab Sci 1999; 36:365–406.[Medline]
  20. Wilcken DE, Wilcken B. The natural history of vascular disease in homocystinuria and the effects of treatment. J Inherit Metab Dis 1997;20:295–300.[Medline]
  21. Yap S, Naughten E. Homocystinuria due to cystathionine beta-synthase deficiency in Ireland: 25 years' experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J Inherit Metab Dis 1998;21:738–47.[Medline]
  22. Kluijtmans LA, Boers GH, Kraus JP, et al. The molecular basis of cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and on response to treatment. Am J Hum Genet 1999;65:59–67.[Medline]
  23. Boushey CJ, Beresford SA, 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;274:1049–57.[Abstract/Free Full Text]
  24. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 1998;49:31–62.[Medline]
  25. Kang SS, Wong PW, Norusis M. Homocysteinemia due to folate deficiency. Metabolism 1987;36:458–62.[Medline]
  26. Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest 1988;81:466–74.
  27. Brattstrom L, Israelsson B, Lindgarde F, Hultberg B. Higher total plasma homocysteine in vitamin B12 deficiency than in heterozygosity for homocystinuria due to cystathionine beta-synthase deficiency. Metabolism 1988;37:175–8.[Medline]
  28. Wilcken DE, Gupta VJ, Reddy SG. Accumulation of sulphur-containing amino acids including cysteine-homocysteine in patients on maintenance haemodialysis. Clin Sci 1980;58:427–30.[Medline]
  29. Arnadottir M, Hultberg B, Nilsson-Ehle P, Thysell H. The effect of reduced glomerular filtration rate on plasma total homocysteine concentration. Scand J Clin Lab Invest 1996;56:41–6.[Medline]
  30. 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;98:2520–6.[Abstract/Free Full Text]
  31. Sardharwalla IB, Fowler B, Robins AJ, Komrower GM. Detection of heterozygotes for homocystinuria. Study of sulphur-containing amino acids in plasma and urine after L-methionine loading. Arch Dis Child 1974;49:553–9.[Abstract/Free Full Text]
  32. Boers GH, Smals AG, Trijbels FJ, et al. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med 1985;313:709–15.[Abstract]
  33. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324:1149–55.[Abstract]
  34. Wilcken DE, Dudman NP, Tyrrell PA, Robertson MR. Folic acid lowers elevated plasma homocysteine in chronic renal insufficiency: possible implications for prevention of vascular disease. Metabolism 1988;37:697–701.[Medline]
  35. Wilcken DE, Reddy SG, Gupta VJ. Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria. Metabolism 1983;32:363–70.[Medline]
  36. Brattstrom L. Vitamins as homocysteine-lowering agents. J Nutr 1996;126:1276S–80S.
  37. Selhub J, Jacques PF, Rosenberg IH, et al. Serum total homocysteine concentrations in the third National Health and Nutrition Examination Survey (1991–1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann Intern Med 1999;131:331–9.[Abstract/Free Full Text]
  38. Clarke R, Collins R. Can dietary supplements with folic acid or vitamin B6 reduce cardiovascular risk? Design of clinical trials to test the homocysteine hypothesis of vascular disease. J Cardiovasc Risk 1998;5:249–55.[Medline]
  39. Morrison HI, Schaubel D, Desmeules M, Wigle DT. Serum folate and risk of fatal coronary heart disease. JAMA 1996;275:1893–6.[Abstract/Free Full Text]
  40. Ford ES, Byers TE, Giles WH. Serum folate and chronic disease risk: findings from a cohort of United States adults. Int J Epidemiol 1998;27:592–8.[Abstract/Free Full Text]
  41. Giles WH, Kittner SJ, Anda RF, Croft JB, Casper ML. Serum folate and risk for ischemic stroke. First National Health and Nutrition Examination Survey epidemiologic follow-up study. Stroke 1995; 26:1166–70.[Abstract/Free Full Text]
  42. Giles WH, Kittner SJ, Croft JB, Anda RF, Casper ML, Ford ES. Serum folate and risk for coronary heart disease: results from a cohort of US adults. Ann Epidemiol 1998;8:490–6.[Medline]
  43. Zeitlin A, Frishman WH, Chang CJ. The association of vitamin B 12 and folate blood levels with mortality and cardiovascular morbidity incidence in the old old: the Bronx Aging Study. Am J Ther 1997;4:275–81.[Medline]
  44. Verhoef P, Rimm EB, Hunter DJ, et al. A common mutation in the methylenetetrahydrofolate reductase gene and risk of coronary heart disease: results among U.S. men. J Am Coll Cardiol 1998;32:353–9.[Abstract/Free Full Text]
  45. Pancharuniti N, Lewis CA, Sauberlich HE, et al. Plasma homocyst(e)ine, folate, and vitamin B-12 concentrations and risk for early-onset coronary artery disease. [Published erratum appears in Am J Clin Nutr 1996;63:609.] Am J Clin Nutr 1994;59:940–8.[Abstract/Free Full Text]
  46. Robinson K, Arheart K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. European COMAC Group. Circulation 1998;97:437–43.[Abstract/Free Full Text]
  47. Chasan-Taber L, Selhub J, Rosenberg IH, et al. A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr 1996;15:136–43.[Abstract]
  48. Schwartz SM, Siscovick DS, Malinow MR, et al. Myocardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene. Circulation 1997;96:412–7.[Abstract/Free Full Text]
  49. Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995;332:286–91.[Abstract/Free Full Text]
  50. Verhoef P, Stampfer MJ, Buring JE, et al. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol 1996;143:845–59.[Abstract/Free Full Text]
  51. Brattstrom L, Israelsson B, Norrving B, et al. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Effects of pyridoxine and folic acid treatment. Atherosclerosis 1990;81:51–60.[Medline]
  52. Molgaard J, Malinow MR, Lassvik C, Holm AC, Upson B, Olsson AG. Hyperhomocyst(e)inaemia: an independent risk factor for intermittent claudication. J Intern Med 1992;231:273–9.[Medline]
  53. Brattstrom L, Lindgren A, Israelsson B, et al. Hyperhomocysteinaemia in stroke: prevalence, cause, and relationships to type of stroke and stroke risk factors. Eur J Clin Invest 1992;22:214–21.[Medline]
  54. Bergmark C, Mansoor MA, Swedenborg J, de Faire U, Svardal AM, Ueland PM. Hyperhomocysteinemia in patients operated for lower extremity ischaemia below the age of 50—effect of smoking and extent of disease. Eur J Vasc Surg 1993;7:391–6.[Medline]
  55. Dalery K, Lussier-Cacan S, Selhub J, Davignon J, Latour Y, Genest J Jr. Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B12, B6, pyridoxal phosphate, and folate. Am J Cardiol 1995;75:1107–11.[Medline]
  56. Hopkins PN, Wu LL, Wu J, et al. Higher plasma homocyst(e)ine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease. Arterioscler Thromb Vasc Biol 1995;15:1314–20.[Abstract/Free Full Text]
  57. Robinson K, Mayer EL, Miller DP, et al. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease. Circulation 1995;92:2825–30.[Abstract/Free Full Text]
  58. Verhoef P, Kok FJ, Kruyssen DA, et al. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. Arterioscler Thromb Vasc Biol 1997;17:989–95.[Abstract/Free Full Text]
  59. Giles WH, Croft JB, Greenlund KJ, Ford ES, Kittner SJ. Total homocyst(e)ine concentration and the likelihood of nonfatal stroke: results from the third National Health and Nutrition Examination Survey, 1988–1994. Stroke 1998;29:2473–7.[Abstract/Free Full Text]
  60. den Heijer M, Blom HJ, Gerrits WB, et al. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis? Lancet 1995;345:882–5.[Medline]
  61. Schmitz C, Lindpaintner K, Verhoef P, Gaziano JM, Buring J. Genetic polymorphism of methylenetetrahydrofolate reductase and myocardial infarction. A case-control study. Circulation 1996;94:1812–4.[Abstract/Free Full Text]
  62. Lalouschek W, Aull S, Serles W, et al. Genetic and nongenetic factors influencing plasma homocysteine levels in patients with ischemic cerebrovascular disease and in healthy control subjects. J Lab Clin Med 1999;133:575–82.[Medline]
  63. Girelli D, Friso S, Trabetti E, et al. Methylenetetrahydrofolate reductase C677T mutation, plasma homocysteine, and folate in subjects from northern Italy with or without angiographically documented severe coronary atherosclerotic disease: evidence for an important genetic-environmental interaction. Blood 1998;91:4158–63.[Abstract/Free Full Text]
  64. McQuillan BM, Beilby JP, Nidorf M, Thompson PL, Hung J. Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS). Circulation 1999;99:2383–8.[Abstract/Free Full Text]
  65. Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberg IH. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996;348:1120–4.[Medline]
  66. Siri PW, Verhoef P, Kok FJ. Vitamins B6, B12, and folate: association with plasma total homocysteine and risk of coronary atherosclerosis. J Am Coll Nutr 1998;17:435–41.[Abstract/Free Full Text]
  67. Shimakawa T, Nieto FJ, Malinow MR, Chambless LE, Schreiner PJ, Szklo M. Vitamin intake: a possible determinant of plasma homocyst(e)ine among middle-aged adults. Ann Epidemiol 1997;7:285–93.[Medline]
  68. Thuillier L, Chadefaux-Vekemans B, Bonnefont JP, et al. Does the polymorphism 677C-T of the 5,10-methylenetetrahydrofolate reductase gene contribute to homocysteine-related vascular disease? J Inherit Metab Dis 1998;21:812–22.[Medline]
  69. Ridker PM, Manson JE, Buring JE, Shih J, Matias M, Hennekens CH. Homocysteine and risk of cardiovascular disease among postmenopausal women. JAMA 1999;281:1817–21.[Abstract/Free Full Text]
  70. Nygard O, Vollset SE, Refsum H, Brattstrom L, Ueland PM. Plasma homocysteine and cardiovascular disease. J Intern Med 1999; 246:425–54.[Medline]
  71. Anderson JL, King GJ, Thomson MJ, et al. 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;30:1206–11.[Abstract]
  72. Dunn J, Title LM, Bata I, et al. Relation of a common mutation in methylenetetrahydrofolate reductase to plasma homocysteine and early onset coronary artery disease. Clin Biochem 1998;31:95–100.[Medline]
  73. Press RD, Beamer N, Evans A, DeLoughery TG, Coull BM. Role of a common mutation in the homocysteine regulatory enzyme methylenetetrahydrofolate reductase in ischemic stroke. Diagn Mol Pathol 1999;8:54–8.[Medline]
  74. Malik NM, Syrris P, Schwartzman R, et al. Methylenetetrahydrofolate reductase polymorphism (C-677T) and coronary artery disease. Clin Sci (Colch) 1998;95:311–5.
  75. Fijnheer R, Roest M, Haas FJ, De Groot PG, Derksen RH. Homocysteine, methylenetetrahydrofolate reductase polymorphism, antiphospholipid antibodies, and thromboembolic events in systemic lupus erythematosus: a retrospective cohort study. J Rheumatol 1998;25:1737–42.[Medline]
  76. Nakata Y, Katsuya T, Takami S, et al. Methylenetetrahydrofolate reductase gene polymorphism: relation to blood pressure and cerebrovascular disease. Am J Hypertens 1998;11:1019–23.[Medline]
  77. Morita H, Kurihara H, Tsubaki S, et al. Methylenetetrahydrofolate reductase gene polymorphism and ischemic stroke in Japanese. Arterioscler Thromb Vasc Biol 1998;18:1465–9.[Abstract/Free Full Text]
  78. Tokgozoglu SL, Alikasifoglu M, Unsal, et al. Methylene tetrahydrofolate reductase genotype and the risk and extent of coronary artery disease in a population with low plasma folate. Heart 1999;81:518–22.[Abstract/Free Full Text]
  79. Gardemann A, Weidemann H, Philipp M, et al. The TT genotype of the methylenetetrahydrofolate reductase C677T gene polymorphism is associated with the extent of coronary atherosclerosis in patients at high risk for coronary artery disease. Eur Heart J 1999;20:584–92.[Abstract/Free Full Text]
  80. Lalouschek W, Aull S, Serles W, et al. C677T MTHFR mutation and factor V Leiden mutation in patients with TIA/minor stroke: a case-control study. Thromb Res 1999;93:61–9.[Medline]
  81. Harmon DL, Doyle RM, Meleady R, et al. Genetic analysis of the thermolabile variant of 5, 10-methylenetetrahydrofolate reductase as a risk factor for ischemic stroke. Arterioscler Thromb Vasc Biol 1999;19:208–11.[Abstract/Free Full Text]
  82. Arai K, Yamasaki Y, Kajimoto Y, et al. Association of methylenetetrahydrofolate reductase gene polymorphism with carotid arterial wall thickening and myocardial infarction risk in NIDDM. Diabetes 1997;46:2102–4.[Medline]
  83. Spence JD, Malinow MR, Barnett PA, Marian AJ, Freeman D, Hegele RA. Plasma homocyst(e)ine concentration, but not MTHFR genotype, is associated with variation in carotid plaque area. Stroke 1999;30:969–73.[Abstract/Free Full Text]
  84. 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;18:1838–43.[Abstract/Free Full Text]
  85. Verhoeff BJ, Trip MD, Prins MH, Kastelein JJ, Reitsma PH. The effect of a common methylenetetrahydrofolate reductase mutation on levels of homocysteine, folate, vitamin B12 and on the risk of premature atherosclerosis. Atherosclerosis 1998;141:161–6.[Medline]
  86. Salooja N, Catto A, Carter A, Tudenham EG, Grant PJ. Methylene tetrahydrofolate reductase C677T genotype and stroke. Clin Lab Haematol 1998;20:357–61.[Medline]
  87. Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997;277:1775–81.[Abstract/Free Full Text]
  88. Kluijtmans LA, van den Heuvel LP, Boers GH, et al. Molecular genetic 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]
  89. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 1998;98:204–10.[Abstract/Free Full Text]
  90. Kozich V, Kraus E, de Franchis R, et al. Hyperhomocysteinemia in premature arterial disease: examination of cystathionine beta-synthase alleles at the molecular level. Hum Mol Genet 1995;4:623–9.[Abstract/Free Full Text]
  91. Tsai MY, Welge BG, Hanson NQ, et al. Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases. Atherosclerosis 1999;143:163–70.[Medline]
  92. Nygard O, Vollset SE, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA 1995;274:1526–33.[Abstract/Free Full Text]
  93. Malinow MR, Levenson J, Giral P, et al. Role of blood pressure, uric acid, and hemorheological parameters on plasma homocyst(e)ine concentration. Atherosclerosis 1995;114:175–83.[Medline]
  94. Sutton-Tyrrell K, Bostom A, Selhub J, Zeigler-Johnson C. High homocysteine levels are independently related to isolated systolic hypertension in older adults. Circulation 1997;96:1745–9.[Abstract/Free Full Text]
  95. Glueck CJ, Shaw P, Lang JE, Tracy T, Sieve-Smith L, Wang Y. Evidence that homocysteine is an independent risk factor for atherosclerosis in hyperlipidemic patients. Am J Cardiol 1995;75:132–6.[Medline]
  96. van den Berg M, Stehouwer CD, Bierdrager E, Rauwerda JA. Plasma homocysteine and severity of atherosclerosis in young patients with lower-limb atherosclerotic disease. Arterioscler Thromb Vasc Biol 1996;16:165–71.[Abstract/Free Full Text]
  97. Hoogeveen EK, Kostense PJ, Beks PJ, et al. Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study. Arterioscler Thromb Vasc Biol 1998;18:133–8.[Abstract/Free Full Text]
  98. Perneger TV, Nieto FJ, Whelton PK, Klag MJ, Comstock GW, Szklo M. A prospective study of blood pressure and serum creatinine. Results from the ‘Clue’ Study and the ARIC Study. JAMA 1993; 269:488–93.[Abstract/Free Full Text]
  99. Klag MJ, Whelton PK, Randall BL, et al. Blood pressure and end-stage renal disease in men. N Engl J Med 1996;334:13–8.[Abstract/Free Full Text]
  100. Ruilope LM. The kidney as part of the cardiovascular system. J Cardiovasc Pharmacol 1999;33:S7–10, S41–3.
  101. Fliser D, Ritz E. Relationship between hypertension and renal function and its therapeutic implications in the elderly. Gerontology 1998;44:123–31.[Medline]
  102. Tracy RE, Strong JP, Newman WP III, Malcom GT, Oalmann MC, Guzman MA. Renovasculopathies of nephrosclerosis in relation to atherosclerosis at ages 25 to 54 years. Kidney Int 1996;49:564–70.[Medline]
  103. Kasiske BL. Relationship between vascular disease and age-associated changes in the human kidney. Kidney Int 1987;31:1153–9.[Medline]
  104. Brattstrom 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;236:633–41.[Medline]
  105. Wollesen F, Brattstrom L, Refsum H, Ueland PM, Berglund L, Berne C. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int 1999;55:1028–35.[Medline]
  106. Bostom AG, Gohh RY, Bausserman L, et al. Serum cystatin C as a determinant of fasting total homocysteine levels in renal transplant recipients with a normal serum creatinine. J Am Soc Nephrol 1999; 10:164–6.[Abstract/Free Full Text]
  107. Norlund L, Grubb A, Fex G, et al. The increase of plasma homocysteine concentrations with age is partly due to the deterioration of renal function as determined by plasma cystatin C. Clin Chem Lab Med 1998;36:175–8.[Medline]
  108. Bostom AG, Lathrop L. Hyperhomocysteinemia in end-stage renal disease: prevalence, etiology, and potential relationship to arteriosclerotic outcomes. Kidney Int 1997;52:10–20.[Medline]
  109. 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]
  110. Bostom A, Brosnan JT, Hall B, Nadeau MR, Selhub J. Net uptake of plasma homocysteine by the rat kidney in vivo. Atherosclerosis 1995;116:59–62.[Medline]
  111. Bostom AG, Bausserman L, Jacques PF, Liaugaudas G, Selhub J, Rosenberg IH. Cystatin C as a determinant of fasting plasma total homocysteine levels in coronary artery disease patients with normal serum creatinine. Arterioscler Thromb Vasc Biol 1999;19:2241–4.[Abstract/Free Full Text]
  112. Stehouwer CD, Gall MA, Hougaard P, Jakobs C, Parving HH. Plasma homocysteine concentration predicts mortality in non-insulin-dependent diabetic patients with and without albuminuria. Kidney Int 1999;55:308–14.[Medline]
  113. Taniwaki H, Nishizawa Y, Kawagishi T, et al. Decrease in glomerular filtration rate in Japanese patients with type 2 diabetes is linked to atherosclerosis. Diabetes Care 1998;21:1848–55.[Abstract]
  114. Ray JG. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med 1998;158:2101–6.[Abstract/Free Full Text]
  115. Gemmati D, Previati M, Serino ML, et al. Low folate levels and thermolabile methylenetetrahydrofolate reductase as primary determinant of mild hyperhomocystinemia in normal and thromboembolic subjects. Arterioscler Thromb Vasc Biol 1999;19:1761–7.[Abstract/Free Full Text]
  116. Eichinger S, Stumpflen A, Hirschl M, et al. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998;80:566–9.[Medline]
  117. Deloughery TG, Evans A, Sadeghi A, et al. Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine metabolism and late-onset vascular disease. Circulation 1996; 94:3074–8.[Abstract/Free Full Text]
  118. Kluijtmans LA, den Heijer M, Reitsma PH, Heil SG, Blom HJ, Rosendaal FR. Thermolabile methylenetetrahydrofolate reductase and factor V Leiden in the risk of deep-vein thrombosis. Thromb Haemost 1998;79:254–8.[Medline]
  119. Salden A, Keeney S, Hay CR, Cumming AM. The C677T MTHFR variant and the risk of venous thrombosis. Br J Haematol 1997; 99:472 (letter).[Medline]
  120. Brown K, Luddington R, Baglin T. Effect of the MTHFRC677T variant on risk of venous thromboembolism: interaction with factor V Leiden and prothrombin (F2G20210A) mutations. Br J Haematol 1998;103:42–4.[Medline]
  121. Akar N, Akar E, Misirlioglu M, Avcu F, Yalcin A, Cin S. Search for genetic factors favoring thrombosis in Turkish population. Thromb Res 1998;92:79–82.[Medline]
  122. Alhenc-Gelas M, Arnaud E, Nicaud V, et al. Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes. Thromb Haemost 1999;81:506–10.[Medline]
  123. Philipp CS, Dilley A, Saidi P, et al. Deletion polymorphism in the angiotensin-converting enzyme gene as a thrombophilic risk factor after hip arthroplasty. Thromb Haemost 1998;80:869–73.[Medline]
  124. Rintelen C, Mannhalter C, Lechner K, et al. No evidence for an increased risk of venous thrombosis in patients with factor V Leiden by the homozygous 677 C to T mutation in the methylenetetrahydrofolate-reductase gene. Blood Coagul Fibrinolysis 1999;10:101–5.[Medline]
  125. Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677°Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. Thromb Haemost 1997;77:818–21.[Medline]
  126. Franco RF, Morelli V, Lourenco D, et al. A second mutation in the methylenetetrahydrofolate reductase gene and the risk of venous thrombotic disease. Br J Haematol 1999;105:556–9.[Medline]
  127. Cattaneo M, Tsai MY, Bucciarelli P, et al. A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (factor V:Q506). Arterioscler Thromb Vasc Biol 1997;17:1662–6.[Abstract/Free Full Text]
  128. 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;97:804–6.[Medline]
  129. Legnani C, Palareti G, Grauso F, et al. Hyperhomocyst(e)inemia and a common methylenetetrahydrofolate reductase mutation (Ala223Val MTHFR) in patients with inherited thrombophilic coagulation defects. Arterioscler Thromb Vasc Biol 1997;17:2924–9.[Abstract/Free Full Text]
  130. Margaglione M, D'Andrea G, d'Addedda M, et al. The methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the FV Leiden and the prothrombin A20210 mutation. Thromb Haemost 1998; 79:907–11.[Medline]
  131. Celermajer DS, Sorensen K, Ryalls M, et al. Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents. J Am Coll Cardiol 1993;22:854–8.[Abstract]
  132. Bellamy MF, McDowell IF, Ramsey MW, Brownlee M, Newcombe RG, Lewis MJ. Oral folate enhances endothelial function in hyperhomocysteinaemic subjects. Eur J Clin Invest 1999;29:659–62.[Medline]
  133. Kanani PM, Sinkey CA, Browning RL, Allaman M, Knapp HR, Haynes WG. Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. Circulation 1999;100:1161–8.[Abstract/Free Full Text]
  134. Chambers JC, McGregor A, Jean-Marie J, Obeid OA, Kooner JS. Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy. Circulation 1999;99:1156–60.[Abstract/Free Full Text]
  135. Schachinger V, Britten MB, Elsner M, Walter DH, Scharrer I, Zeiher AM. A positive family history of premature coronary artery disease is associated with impaired endothelium-dependent coronary blood flow regulation. Circulation 1999;100:1502–8.[Abstract/Free Full Text]
  136. Verhaar MC, Rabelink TJ. Future for folates in cardiovascular disease. Eur J Clin Invest 1999;29:657–8.[Medline]
  137. Usui M, Matsuoka H, Miyazaki H, Ueda S, Okuda S, Imaizumi T. Endothelial dysfunction by acute hyperhomocyst(e)inaemia: restoration by folic acid. Clin Sci (Colch) 1999;96:235–9.
  138. Wang XL, Wang J, McCredie RM, Wilcken DE. Polymorphisms of factor V, factor VII, and fibrinogen genes. Relevance to severity of coronary artery disease. Arterioscler Thromb Vasc Biol 1997;17: 246–51.[Abstract/Free Full Text]
  139. Wilcken DEL, Wilcken BB. Vitamins and homocysteine in cardiovascular disease and aging. Ann N Y Acad Sci 1998;854:361–70.[Medline]
Received for publication November 22, 1999. Accepted for publication March 1, 2000.




This article has been cited by other articles:


Home page
 Eur Heart JHome page
C. Antoniades, A. S. Antonopoulos, D. Tousoulis, K. Marinou, and C. Stefanadis
Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials
Eur. Heart J., January 1, 2009; 30(1): 6 - 15.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
C. Liu, Q. Wang, H. Guo, M. Xia, Q. Yuan, Y. Hu, H. Zhu, M. Hou, J. Ma, Z. Tang, et al.
Plasma S-Adenosylhomocysteine Is a Better Biomarker of Atherosclerosis Than Homocysteine in Apolipoprotein E-Deficient Mice Fed High Dietary Methionine
J. Nutr., February 1, 2008; 138(2): 311 - 315.
[Abstract] [Full Text] [PDF]

Home page
 Appl. Environ. Microbiol.Home page
A. Wegkamp, W. van Oorschot, W. M. de Vos, and E. J. Smid
Characterization of the Role of para-Aminobenzoic Acid Biosynthesis in Folate Production by Lactococcus lactis
Appl. Envir. Microbiol., April 15, 2007; 73(8): 2673 - 2681.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. Cohen-Salmon, B. Regnault, N. Cayet, D. Caille, K. Demuth, J.-P. Hardelin, N. Janel, P. Meda, and C. Petit
Connexin30 deficiency causes instrastrial fluid-blood barrier disruption within the cochlear stria vascularis
PNAS, April 10, 2007; 104(15): 6229 - 6234.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
M. N Haan, J. W Miller, A. E Aiello, R. A Whitmer, W. J Jagust, D. M Mungas, L. H Allen, and R. Green
Homocysteine, B vitamins, and the incidence of dementia and cognitive impairment: results from the Sacramento Area Latino Study on Aging
Am. J. Clinical Nutrition, February 1, 2007; 85(2): 511 - 517.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurol. Neurosurg. PsychiatryHome page
A Pezzini, M Grassi, E Del Zotto, D Assanelli, S Archetti, R Negrini, L Caimi, and A Padovani
Interaction of homocysteine and conventional predisposing factors on risk of ischaemic stroke in young people: consistency in phenotype-disease analysis and genotype-disease analysis
J. Neurol. Neurosurg. Psychiatry, October 1, 2006; 77(10): 1150 - 1156.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
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]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
J. D. Symons, U. B. Zaid, C. N. Athanassious, A. E. Mullick, S. R. Lentz, and J. C. Rutledge
Influence of Folate on Arterial Permeability and Stiffness in the Absence or Presence of Hyperhomocysteinemia
Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 814 - 818.
[Abstract] [Full Text] [PDF]

Home page
 Mayo Clin Proc.Home page
I. J. Kullo, G. Li, L. F. Bielak, K. R. Bailey, P. F. Sheedy II, P. A. Peyser, S. T. Turner, and S. L. R. Kardia
Association of Plasma Homocysteine With Coronary Artery Calcification in Different Categories of Coronary Heart Disease Risk
Mayo Clin. Proc., February 1, 2006; 81(2): 177 - 182.
[Abstract] [Full Text] [PDF]

Home page
 BMJHome page
S. J Lewis, S. Ebrahim, and G. Davey Smith
Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?
BMJ, November 5, 2005; 331(7524): 1053.
[Abstract] [Full Text] [PDF]

Home page
 Vasc MedHome page
I. Qureshi, H. Chen, A. T Brown, R. Fitzgerald, X. Zhang, J. Breckenridge, R. Kazi, A. J Crocker, M. C Stuhlingexsr, K. Lin, et al.
Homocysteine-induced vascular dysregulation is mediated by the NMDA receptor
Vascular Medicine, August 1, 2005; 10(3): 215 - 223.
[Abstract] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
C. Williams, B. A Kingwell, K. Burke, J. McPherson, and A. M Dart
Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype
Am. J. Clinical Nutrition, July 1, 2005; 82(1): 26 - 31.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
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]

Home page
 Am. J. Clin. Nutr.Home page
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]

Home page
 J. Biol. Chem.Home page
G. Lund, L. Andersson, M. Lauria, M. Lindholm, M. F. Fraga, A. Villar-Garea, E. Ballestar, M. Esteller, and S. Zaina
DNA Methylation Polymorphisms Precede Any Histological Sign of Atherosclerosis in Mice Lacking Apolipoprotein E
J. Biol. Chem., July 9, 2004; 279(28): 29147 - 29154.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
P. Quadri, C. Fragiacomo, R. Pezzati, E. Zanda, G. Forloni, M. Tettamanti, and U. Lucca
Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia
Am. J. Clinical Nutrition, July 1, 2004; 80(1): 114 - 122.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
F. Bieswal, S. M. Hay, C. McKinnon, B. Reusens, M. Cuignet, W. D. Rees, and C. Remacle
Prenatal Protein Restriction Does Not Affect the Proliferation and Differentiation of Rat Preadipocytes
J. Nutr., June 1, 2004; 134(6): 1493 - 1499.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
W. K. Al-Delaimy, K. M. Rexrode, F. B. Hu, C. M. Albert, M. J. Stampfer, W. C. Willett, and J. E. Manson
Folate Intake and Risk of Stroke Among Women
Stroke, June 1, 2004; 35(6): 1259 - 1263.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
E. Nurk, G. S Tell, S. E Vollset, O. Nygard, H. Refsum, R. M Nilsen, and P. M Ueland
Changes in lifestyle and plasma total homocysteine: the Hordaland Homocysteine Study
Am. J. Clinical Nutrition, May 1, 2004; 79(5): 812 - 819.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
A. M. Troen, E. Lutgens, D. E. Smith, I. H. Rosenberg, and J. Selhub
The atherogenic effect of excess methionine intake
PNAS, December 9, 2003; 100(25): 15089 - 15094.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
J. Sundstrom, L. Sullivan, R. B. D'Agostino, P. F. Jacques, J. Selhub, I. H. Rosenberg, P. W.F. Wilson, D. Levy, and R. S. Vasan
Plasma Homocysteine, Hypertension Incidence, and Blood Pressure Tracking: The Framingham Heart Study
Hypertension, December 1, 2003; 42(6): 1100 - 1105.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
M. Wolters, S. Hermann, and A. Hahn
B vitamin status and concentrations of homocysteine and methylmalonic acid in elderly German women
Am. J. Clinical Nutrition, October 1, 2003; 78(4): 765 - 772.
[Abstract] [Full Text] [PDF]

Home page
 British Journal of Diabetes & Vascular DiseaseHome page
F. Wotherspoon, D. W Laight, K. M Shaw, and M. H Cummings
Review: Homocysteine, endothelial dysfunction and oxidative stress in type 1 diabetes mellitus
The British Journal of Diabetes & Vascular Disease, September 1, 2003; 3(5): 334 - 340.
[Abstract] [PDF]

Home page
 Clin. Chem.Home page
C. Infante-Rivard, G.-E. Rivard, R. Gauthier, and Y. Theoret
Unexpected Relationship between Plasma Homocysteine and Intrauterine Growth Restriction
Clin. Chem., September 1, 2003; 49(9): 1476 - 1482.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
A. Deussen
Adenosine--the missing link to understanding homocysteine pathogenicity or more smoke on the horizon?
Cardiovasc Res, August 1, 2003; 59(2): 259 - 261.
[Full Text] [PDF]

Home page
 Appl. Environ. Microbiol.Home page
W. Sybesma, M. Starrenburg, M. Kleerebezem, I. Mierau, W. M. de Vos, and J. Hugenholtz
Increased Production of Folate by Metabolic Engineering of Lactococcus lactis
Appl. Envir. Microbiol., June 1, 2003; 69(6): 3069 - 3076.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
L. El-Khairy, S. E. Vollset, H. Refsum, and P. M. Ueland
Plasma Total Cysteine, Mortality, and Cardiovascular Disease Hospitalizations: The Hordaland Homocysteine Study
Clin. Chem., June 1, 2003; 49(6): 895 - 900.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
G. R. Steenge, P. Verhoef, and M. B. Katan
Betaine Supplementation Lowers Plasma Homocysteine in Healthy Men and Women
J. Nutr., May 1, 2003; 133(5): 1291 - 1295.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
J. M Hodgson, V. Burke, L. J Beilin, K. D Croft, and I. B Puddey
Can black tea influence plasma total homocysteine concentrations?
Am. J. Clinical Nutrition, April 1, 2003; 77(4): 907 - 911.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
Q. Shi, J. E. Savage, S. J. Hufeisen, L. Rauser, E. Grajkowska, P. Ernsberger, J. T. Wroblewski, J. H. Nadeau, and B. L. Roth
L-Homocysteine Sulfinic Acid and Other Acidic Homocysteine Derivatives Are Potent and Selective Metabotropic Glutamate Receptor Agonists
J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 131 - 142.
[Abstract] [Full Text]

Home page
 CirculationHome page
P. L. Rensma, A. J. Apperloo, P. E. de Jong, Y.-F. Chen, P.-L. Li, and A.-P. Zou
Why Does Elevated Plasma Homocysteine Result in Severe Microvascular Injury, but Not Glomerular Damage? * Response
Circulation, March 25, 2003; 107 (11): e77 - e77.
[Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
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]

Home page
 Int J EpidemiolHome page
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]

Home page
 Am. J. Clin. Nutr.Home page
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]

Home page
 Am. J. Clin. Nutr.Home page
Q. Yang and J D. Erickson
Influence of reporting error on the relation between blood folate concentrations and reported folic acid-containing dietary supplement use among reproductive-aged women in the United States
Am. J. Clinical Nutrition, January 1, 2003; 77(1): 196 - 203.
[Abstract] [Full Text] [PDF]

Home page
 ASH Education BookHome page
R. Carmel, R. Green, D. S. Rosenblatt, and D. Watkins
Update on Cobalamin, Folate, and Homocysteine
Hematology, January 1, 2003; 2003(1): 62 - 81.
[Abstract] [Full Text] [PDF]

Home page
 Am J EpidemiolHome page
U. Lim and P. A. Cassano
Homocysteine and Blood Pressure in the Third National Health and Nutrition Examination Survey, 1988-1994
Am. J. Epidemiol., December 15, 2002; 156(12): 1105 - 1113.
[Abstract] [Full Text] [PDF]

Home page
 Journal of Renin-Angiotensin-Aldosterone SystemHome page
Pacific Study Group and B. Neal
Effects of the vasopeptidase inhibitor, omapatrilat, in 723 patients with coronary heart disease
Journal of Renin-Angiotensin-Aldosterone System, December 1, 2002; 3(4): 270 - 276.
[Abstract] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
P. Verhoef, W. J Pasman, T. van Vliet, R. Urgert, and M. B Katan
Contribution of caffeine to the homocysteine-raising effect of coffee: a randomized controlled trial in humans
Am. J. Clinical Nutrition, December 1, 2002; 76(6): 1244 - 1248.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
L. I Mennen, G. P. de Courcy, J.-C. Guilland, V. Ducros, S. Bertrais, J.-P. Nicolas, M. Maurel, M. Zarebska, A. Favier, C. Franchisseur, et al.
Homocysteine, cardiovascular disease risk factors, and habitual diet in the French Supplementation with Antioxidant Vitamins and Minerals Study
Am. J. Clinical Nutrition, December 1, 2002; 76(6): 1279 - 1289.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
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]

Home page
 BMJHome page
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]

Home page
 J Am Coll CardiolHome page
G. Schnyder, Y. Flammer, M. Roffi, R. Pin, and O. M. Hess
Plasma homocysteine levels and late outcome after coronary angioplasty
J. Am. Coll. Cardiol., November 20, 2002; 40(10): 1769 - 1776.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
B. Borroni, C. Agosti, A.F. Panzali, M. Di Luca, A. Padovani, J.W. Miller, R. Green, D.M. Mungas, B.R. Reed, and W.J. Jagust
Homocysteine, vitamin B6, and vascular disease in patients with AD
Neurology, November 12, 2002; 59(9): 1475 - 1476.
[Full Text] [PDF]

Home page
 JAMAHome page
Homocysteine Studies Collaboration
Homocysteine and Risk of Ischemic Heart Disease and Stroke: A Meta-analysis
JAMA, October 23, 2002; 288(16): 2015 - 2022.
[Abstract] [Full Text] [PDF]

Home page
 JAMAHome page
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]

Home page
 Eur Heart JHome page
P. O'Callaghan, R. Meleady, T. Fitzgerald, I. Graham, and European COMAC group
Smoking and plasma homocysteine
Eur. Heart J., October 2, 2002; 23(20): 1580 - 1586.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
N. Li, F.-X. Yi, E. Rute, D. X. Zhang, G. R. Slocum, and A.-P. Zou
Effects of homocysteine on intracellular nitric oxide and superoxide levels in the renal arterial endothelium
Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1237 - H1243.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
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]

Home page
 J. Nutr.Home page
E. B. Feldman
The Scientific Evidence for a Beneficial Health Relationship Between Walnuts and Coronary Heart Disease
J. Nutr., May 1, 2002; 132(5): 1062S - 1101.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
D. V. Chirieac, T. A. Pearson, A. G. Bostom, B. Sharaf, N. Miele, G. Schnyder, and Z. G. Turi
B Vitamins and Restenosis after Coronary Angioplasty
N. Engl. J. Med., April 4, 2002; 346(14): 1093 - 1095.
[Full Text] [PDF]

Home page
 Diabetes CareHome page
J.-M. Gonzalez-Clemente, R. Deulofeu, J. Mitjavila, G. Galdon, E. Ortega, A. Caixas, G. Gimenez-Perez, and D. Mauricio
Plasma Homocysteine Is not Increased in Microalbuminuric Patients With Type 2 Diabetes Without Clinical Cardiovascular Disease
Diabetes Care, March 1, 2002; 25(3): 632 - 633.
[Full Text] [PDF]

Home page
 StrokeHome page
V. J. Howard, E. G. Sides, G. C. Newman, S. N. Cohen, G. Howard, M. R. Malinow, and J. F. Toole
Changes in Plasma Homocyst(e)ine in the Acute Phase After Stroke
Stroke, February 1, 2002; 33(2): 473 - 478.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
C.-J. Hung, P.-C. Huang, S.-C. Lu, Y.-H. Li, H.-B. Huang, B.-F. Lin, S.-J. Chang, and H.-F. Chou
Plasma Homocysteine Levels in Taiwanese Vegetarians Are Higher than Those of Omnivores
J. Nutr., February 1, 2002; 132(2): 152 - 158.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
P. F. Jacques, R. Kalmbach, P. J. Bagley, G. T. Russo, G. Rogers, P. W. F. Wilson, I. H. Rosenberg, and J. Selhub
The Relationship between Riboflavin and Plasma Total Homocysteine in the Framingham Offspring Cohort Is Influenced by Folate Status and the C677T Transition in the Methylenetetrahydrofolate Reductase Gene
J. Nutr., February 1, 2002; 132(2): 283 - 288.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
N. Li, Y.-F. Chen, and A.-P. Zou
Implications of Hyperhomocysteinemia in Glomerular Sclerosis in Hypertension
Hypertension, February 1, 2002; 39(2): 443 - 448.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
D. M Kerins, M. J Koury, A. Capdevila, S. Rana, and C. Wagner
Plasma S-adenosylhomocysteine is a more sensitive indicator of cardiovascular disease than plasma homocysteine
Am. J. Clinical Nutrition, December 1, 2001; 74(6): 723 - 729.
[Abstract] [Full Text]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
S. Yap, G. H.J. Boers, B. Wilcken, D. E.L. Wilcken, D. P. Brenton, P. J. Lee, J. H. Walter, P. M. Howard, and E. R. Naughten
Vascular Outcome in Patients With Homocystinuria due to Cystathionine {beta}-Synthase Deficiency Treated Chronically: A Multicenter Observational Study
Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 2080 - 2085.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
G. J. Cuskelly, P. W. Stacpoole, J. Williamson, T. G. Baumgartner, and J. F. Gregory III
Deficiencies of folate and vitamin B6 exert distinct effects on homocysteine, serine, and methionine kinetics
Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1182 - E1190.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
K. de Meer, F. Stam, and C. van Guldener
Hyperhomocysteinemia and cardiovascular disease
Am. J. Clinical Nutrition, May 1, 2001; 73(5): 992 - 993.
[Full Text]

Home page
 Am. J. Clin. Nutr.Home page
J. M Scott
Homocysteine and cardiovascular risk
Am. J. Clinical Nutrition, August 1, 2000; 72(2): 333 - 334.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Brattström, L.
Right arrow Articles by Wilcken, D. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brattström, L.
Right arrow Articles by Wilcken, D. E.
Agricola
Right arrow Articles by Brattström, L.
Right arrow Articles by Wilcken, D. E.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS