Homocysteine and Risk of Premature Coronary Heart Disease

Gallagher, Paula; Meleady, Raymond; Shields, Denis C.; Tan, Kaixuan; McMaster, Dorothy; Rozen, Rima; Evans, Alun; Graham, Ian; Whitehead, Alexander S.

doi:10.1161/01.cir.94.9.2154

Cited by 210 publications

(108 citation statements)

References 23 publications

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“…There have been reports of increased risk for cardiovascular disease in persons with the MTHFR C677T mutation (Morita et al 1997;Kang et al 1988Kang et al , 1991Gallagher et al 1996;Kluijtmans et al 1996). In one study, the presence of the MTHFR C677T mutation in a group of patients with venous thromboembolic disease in various parts of the body, mainly in deep large veins was examined (Arruda et al 1997).…”

Section: Discussionmentioning

confidence: 99%

“…A number of investigations have been done to identify whether the thermolabile mutant, MTHFR C677T causes an increased risk for cardiovascular disease. Some results suggest such a correlation (Morita et al 1997;Kang et al 1988Kang et al , 1991Gallagher et al 1996;Kluijtmans et al 1996), whereas others do not (Verhoef et al 1997;Anderson et al 1997;Ma et al 1996;Deloughery et al 1996;van Bockxmeer et al 1997;Christensen et al 1997;Wilcken et al 1996;Adams et al 1996;Brugada & Marian;1997). Arruda et al have shown that there is a correlation between homozygosity for the MTHFR C677T mutation and venous thromboembolic disease (Arruda et al 1997).…”

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confidence: 99%

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Hyperhomocysteinemia and the MTHFR C677T mutation in central retinal vein occlusion

Larsson

Hultberg

Hillarp³

2000

Acta Ophthalmologica Scandinavica

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ABSTRACT.Background: Hyperhomocysteinemia is a factor that predisposes to thrombosis, and the C677T mutation in methylene-tetrahydrofolate reductase (MTHFR) is known to give increased plasma homocysteine. We wanted to investigate if these factors were overrepresented in a group of patients with central retinal vein occlusion. Methods: 116 patients with a history of central retinal vein occlusion were examined for the presence of hyperhomocysteinemia and the MTHFR C677T mutation. Results: Compared to the control groups, there was no significant increase, neither in plasma homocysteine nor in the frequency of the MTHFR C677T mutation in the patients. Even when we looked selectively at the young patients, age less than 50 years, no difference could be detected. Conclusion: It seems that neither hyperhomocysteinemia nor the MTHFR C677T mutation is an important risk factor for the aetiology of central retinal vein occlusion.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Hyperhomocysteinemia and the MTHFR C677T mutation in central retinal vein occlusion

Larsson

Hultberg

Hillarp³

2000

Acta Ophthalmologica Scandinavica

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“…12 Recent studies have investigated this mutation as a genetic risk factor for spina bifida [13][14][15] and cardiovascular disease. [16][17][18][19][20] All studies indicate that homozygotes for this transition have mildly elevated plasma homocysteine, especially in circumstances of low folate status 21,22 In this report, we describe the identification of two missense and two nonsense mutations in the MTHFR gene in four unrelated families from Turkish/Greek ancestry with severe MTHFR deficiency. Furthermore, our data contribute to the genotype/phenotype correlations in this metabolic disease.…”

Section: Introductionmentioning

confidence: 89%

Identification of four novel mutations in severe methylenetetrahydrofolate reductase deficiency

Wendel

et al. 1998

Eur J Hum Genet

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Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is an inborn error of folate metabolism, and is inherited as an autosomal recessive trait. MTHFR is a key enzyme in folate-dependent remethylation of homocysteine, and reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Patients with this severe enzymatic deficiency are biochemically characterised by homocystinuria and hypomethioninaemia, and may suffer from neurological abnormalities, mental retardation and premature vascular disease. Here we report the molecular basis of severe MTHFR deficiency in four unrelated families from Turkish/Greek ancestry. By use of reverse-transcriptase (RT)-PCR, subsequently followed by direct sequencing analysis, we were able to identify four novel mutations in the MTHFR gene: two missense (983A®G; 1027T®G) and two nonsense (1084C®T; 1711C®T) mutations. Furthermore, a splice variant containing a premature termination codon, was observed in one patient, probably as a secondary effect of the 1027T®G missense mutation. The ongoing identification and characterisation of mutations in the MTHFR gene will provide further insight into the heterogeneity of the clinical phenotype in severe MTHFR deficiency.

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“…Indeed, the C677T mutation of the MTHFR gene is not unequivocally associated with increased cardiovascular risk. Some studies support the concept that C677T polymorphism in the MTHFR gene increases the risk (Gallagher et al, 1996;Kluijtmans et al, 1996;Ou et al, 1998) but others do not (Adams et al, 1996;Ma et al, 1996;Schmitz et al, 1996;Verhoef et al, 1997a;Wilcken et al, 1996). Nevertheless, the homozygote mutant genotype leads to hyperhomocysteinemia only when plasma folate status is low in healthy subjects and in patients with cardiovascular disease, thus subjects with this MTHFR mutation may be sensitive to low folate intake (Christensen et al, 1996; Verhoef et al, 1997a).…”

Section: Genetic And/or Nutritional Factor-mediated Hyperhomocysteinementioning

confidence: 99%

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

228

147

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SUMMARY:Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N 5,10 -methylenetetrahydrofolate reductase, and vitamin B 6 deficiency, perhaps associated with cystathionine ␤-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease. (Lab Invest 2001, 81:645-672).C ardiovascular diseases remain the leading cause of mortality in Western populations. Hyperlipoproteinemia, hypertension, diabetes, obesity, and tobacco smoking are the main risk factors for atherosclerosis and its thrombotic complications. However, these factors alone cannot account for all of the deaths caused by vascular pathologies.As early as 1969, clinical studies conducted in homocystinuric children revealed the importance of severe hyperhomocysteinemia in premature development of atherosclerosis and thromboembolism (McCully, 1983). According to numerous retrospective case-controlled studies, moderate increases in plasma homocysteine, which can be precisely quantitated by high performance liquid chromatography (HPLC), raise the risk for cardiovascular disease 2-fold, after adjusting for classic risk factors. Moreover, up to 20% to 40% of patients with vascular pathologies present moderate to intermediate hyperhomocysteinemia. However, results from prospective studies are inconsistent. Additionally, molecular mechanisms underlying hyperhomocysteinemia-induced vascular diseas...

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Homocysteine and Risk of Premature Coronary Heart Disease

Cited by 210 publications

References 23 publications

Hyperhomocysteinemia and the MTHFR C677T mutation in central retinal vein occlusion

Hyperhomocysteinemia and the MTHFR C677T mutation in central retinal vein occlusion

Identification of four novel mutations in severe methylenetetrahydrofolate reductase deficiency

Impaired Homocysteine Metabolism and Atherothrombotic Disease

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