The 677C→T mutation in the methylenetetrahydrofolate reductase gene: associations with plasma total homocysteine levels and risk of coronary atherosclerotic disease
Introduction
Elevated plasma total homocysteine (tHcy), an independent risk factor for atherosclerotic vascular disease 1, 2, is partly genetically determined 3, 4. Homocysteine is formed from methionine and is either catabolized in the vitamin B6-dependent transsulfuration pathway or remethylated to methionine. This latter reaction is catalyzed by the enzyme methionine synthase, which requires 5-methyltetrahydrofolate (5-methyl-THF) as substrate and vitamin B12 as cofactor. 5-Methyl-THF is formed by the reduction of 5,10-methylene-THF by 5,10-methylene-THF reductase (MTHFR), which is a regulating enzyme in homocysteine metabolism [5]. Consequently, deficiencies of MTHFR may result in elevation of plasma tHcy.
In 1988, Kang et al. 6, 7discovered a variant of the MTHFR enzyme, characterized by a specific enzyme activity of approximately 50% of the normal activity. The enzyme appeared to be thermolabile, providing an opportunity to distinguish between this variant and the normal enzyme. Furthermore, they and others described that thermolability of MTHFR was common in the normal population (5%), associated with raised tHcy levels, and increased risk of coronary artery disease 8, 9, 10. Recently, a 677C→T mutation was detected in the MTHFR gene, and homozygosity for this mutation was associated with decreased specific enzyme activity, increased thermolability, and elevated tHcy [11], mainly in subjects with low levels of plasma folate 12, 13. Several investigations have now studied whether homozygosity for the MTHFR 677C→T mutation is a risk factor for cardiovascular disease. Three studies found a two- to threefold increased risk for atherosclerotic vascular disease 14, 15, 16, one study found a twofold increased risk for thrombotic vascular disease [17], but seven other studies observed virtually no association or even a slight inverse association between homozygosity for the mutation and risk of cardiovascular disease 18, 24.
In the present study, we investigated the frequency of 677C→T genotype and its association with tHcy levels before and after methionine loading in subjects with severely occluded coronaries and normal coronaries, and in controls from the general population. Since an adequate folate status may counterbalance the defective production of 5-methyl-THF in subjects with thermolabile MTHFR, we also studied the interactive effect of genotype and erythrocyte folate status on plasma tHcy level and on risk of coronary atherosclerosis.
Section snippets
Study population
A case-control study was conducted from June 1992 to June 1994. Cases and one control group were selected from patients aged 25–65 years, who underwent coronary angiography in the Zuiderziekenhuis Hospital in Rotterdam, the Netherlands. Subjects with either severe coronary occlusions (referred to as cases) or without substantial coronary occlusions (referred to as coronary controls) were included. A second control group was drawn from the general population and comprised subjects with no
Characteristics and tHcy
Age, gender, coronary risk factors and plasma tHcy levels of the cases and the two control groups are shown in Table 1. Except for age and gender, all other risk factors were adjusted for age and gender. In comparison with each of the control groups, cases had a statistically significant higher mean age, proportion of hypertensive subjects, mean level of total/HDL cholesterol, mean serum level of triglycerides and mean pack years of smoking. In addition, cases had a statistically significant
Discussion
In the present investigation, we showed that homozygosity for the 677C→T mutation in the MTHFR gene was associated with raised plasma tHcy levels, particularly when measured in the fasting state. However, +/+ genotype was not associated with increased risk of severe coronary atherosclerosis. Elevation of tHcy in +/+ subjects was limited to those with erythrocyte folate levels below the median of the study population. However, we have not been able to prove the hypothesis that the combination of
Acknowledgements
The study was supported by a grant from the Netherlands Organization for Scientific Research (project 904-61-047). The authors would like to express their gratitude to Drs A.A.A. Bak, S.C. Balduw, G.J. van Beek, M.P. Freericks, F.M.A. Harms, R. van Mechelen, W.M. Muijs van de Moer and R. Wardeh for their support in selecting the participants. We thank Dr D.E. Grobbee and Dr J.C.M. Witteman for their help in designing and conducting of the study. We are very grateful to Annelies Legters, the
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Methylenetetrahydrofolate reductase polymorphism: An independent risk determinant of coronary heart disease in an endogamous population from Delhi (India)
2010, e-SPENCitation Excerpt :The frequency of MTHFR 677T allele observed in the presently studied population (cases 27% & control 17%) is quite high as compared to that reported in Tamil population (cases – 11.5% & control – 7.5%) by Angeline et al.12, and also a study from Pune (cases – 19% & control – 18%) by Mukherjee et al.13 Frequency of TT genotype (cases – 13% and 12% in controls) observed in the present study is quite high and is in concordance with earlier studies conducted among French Canadian (12%), European (9.7%), Australian (10%) and Italian (19%) populations.33–35 Going by the higher odds ratio value for T allele of MTHFR C677T polymorphism, the TT genotype is expected to be more frequent among cases as it is likely to be more deleterious.
C677T Polymorphism of the 5,10 MTHFR Gene in Young Mexican Subjects with ST-Elevation Myocardial Infarction
2010, Archives of Medical ResearchMTHFR and the risk for cerebral venous thrombosis- a meta-analysis
2010, Thrombosis ResearchCitation Excerpt :High plasma levels of homocysteine result from the interaction between genetic and acquired factors (e.g. B-vitamins deficiencies) [25]. The 677C>T polymorphism is associated with decreased enzyme activity and mildly elevated homocysteine plasma levels [26] especially in the presence of low folate [27–29]. Patients with MTHFR mutation and low folate levels presented, in one study, the highest fasting homocysteine levels which were related with an increased risk for CVT.[17].
Association between a single nucleotide polymorphism in MTHFR gene and polycystic ovary syndrome
2009, European Journal of Obstetrics and Gynecology and Reproductive BiologyCitation Excerpt :The methionine supplies the methyl groups for the formation of DNA and protein methylation [13]. Furthermore, the C677T missense variant in the MTHFR, changing from alanine to valine residue, results in perturbation in normal enzymatic activities and leads to high homocysteine and low folate levels in the plasma [14–18]. Although the mechanism is unknown at present, strong association has been found between Hcy levels and CAD, which is found often in PCOS women.
Methionine Synthase Reductase (MTRR) A66G polymorphism is not related to plasma homocysteine concentration and the risk for vascular disease
2009, Experimental and Molecular PathologyMTHFR C677T mutation in central retinal vein occlusion: A case-control study in Chinese population
2008, Thrombosis Research