Research Article| Volume 154, ISSUE 3, P659-666, February 15, 2001

Download started.


The effect of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase gene on homocysteine levels in elderly men and women from the British regional heart study


      Total blood levels of homocysteine (tHcy) have been shown to depend on both environmental and genetic factors, and to be associated with the risk of developing atherosclerosis with its complications of coronary heart disease (CHD) and stroke. In this study, 408 men and 346 women from two towns, Dewsbury and Maidstone were examined for tHcy levels and genotyped for the C677T and the A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene. Blood tHcy was significantly higher in men from the CHD high risk town of Dewsbury (12.7 μmol/l) than in the low CHD risk town of Maidstone (11.5 μmol/l) P<0.001, but not in women (10.7 vs. 10.5 μmol/l), with women in both towns, thus, showing significantly lower tHcy than men. There was no difference between towns in folate or vitamin B12 levels but the conventional inverse relationship with tHcy was seen. Smoking men and women from both towns had significantly higher tHcy and lower folate levels than non-smoking individuals (P<0.001). The frequency of the 677T allele in Dewsbury was 0.35 (95% CI; 0.32–0.39) compared with 0.29 (95% CI; 0.26–0.32) in Maidstone (P<0.01). Similar frequency difference of borderline statistical significance was seen both for men (P=0.054) and women (P=0.048) in both the towns, suggesting a true regional frequency difference. The effect of the 677T on tHcy was highly significant in the group as a whole with the most profound effect seen in men (12.0 μmol/l for CC vs. 14.1 μmol/l for TT, P<0.001). By contrast, there was no significant effect of the A1298C polymorphism on tHcy, folate or vitamin B12 levels, with no evidence for an interaction with the C677T genotype. The regional differences in tHcy levels were still present after the adjustment for folate and vitamin B12 levels, smoking and the effect of the C677T polymorphism. This suggests that there may be other unidentified factors, either environmental or genetic, affecting tHcy levels, and thus potentially having an impact on the risk of developing hyperhomocysteinaemia and CHD. These observations may have a bearing on regional differences in tHcy levels and the variation in CHD risk between regions in the UK.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Boushey C.J
        • Beresford S.A
        • Omenn G.S
        • Motulsky A.G
        A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes.
        J. Am. Med. Assoc. 1995; 274: 1049-1057
        • Graham I.M
        • Daly L.E
        • Refsum H.M
        • et al.
        Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project.
        J. Am. Med. Assoc. 1997; 277: 1775-1781
        • Whincup P.H
        • Refsum H
        • Perry I.J
        • et al.
        Serum total homocysteine and coronary heart disease: prospective study in middle aged men.
        Heart. 1999; 82: 448-454
        • Welch G.N
        • Loscalzo J
        Homocysteine and atherothrombosis.
        New Engl. J. Med. 1998; 338: 1042-1050
        • Avramopoulos D
        • Cox T
        • Kraus J.P
        • Chakravarti A
        • Antonarakis S.E
        Linkage mapping of the cystathionine beta-synthase (CBS) gene on human chromosome 21 using a DNA polymorphism in the 3′ untranslated region.
        Hum. Genet. 1993; 90: 566-568
        • Rosenblatt D.S
        Inherited disorders of folate transport and metabolism.
        in: Scriver C.R Beaudet A.L Sly W.S Valle D Metabolic Basis of Inherited Disease. McGraw-Hill, New York1989: 2049-2064
        • Mudd S.H
        • Skovby F
        Disorders of transulfuration.
        in: Scriver C.R Beaudet A.L Sly W.S Valle D Metabolic Basis of Inherited Disease. McGraw-Hill, New York1989: 693-734
        • Kang S.S
        • Zhou J
        • Wong P.W
        • Kowalisyn J
        • Strokosch G
        Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase.
        Am. J. Hum. Genet. 1988; 43: 414-421
        • Frosst P
        • Blom H.J
        • Milos R
        • et al.
        A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.
        Nat. Genet. 1995; 10: 111-113
        • Brattstrom L
        • Wilcken D.E
        • Ohrvik J
        • Brudin L
        Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinaemia but not to vascular disease: the result of a meta-analysis.
        Circulation. 1998; 98: 2520-2526
        • Gudnason V
        • Stansbie D
        • Scott J
        • Bowron A
        • Nicaud V
        • Humphries S
        C677T (thermolabile alanine/valine) polymorphism in methylenetetrahydrofolate reductase (MTHFR): its frequency and impact on plasma homocysteine concentration in different European populations. EARS group.
        Atherosclerosis. 1998; 136: 347-354
        • van der Put N.M
        • Gabreels F
        • Stevens E.M
        • et al.
        A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?.
        Am. J. Hum. Genet. 1998; 62: 1044-1051
        • Shaper A.G
        • Pocock S.J
        • Walker M
        • Cohen N.M
        • Wale C.J
        • Thomson A.G
        British regional heart study: cardiovascular risk factors in middle-aged men in 24 towns.
        Br. Med. J. Clin. Res. Ed. 1981; 283: 179-186
        • Fiskerstrand T
        • Refsum H
        • Kvalheim G
        • Ueland P.M
        Homocysteine and other thiols in plasma and urine: automated determination and sample stability.
        Clin. Chem. 1993; 39: 263-271
        • Miller S.A
        • Dykes D.D
        • Polesky H.F
        A simple salting out procedure for extracting DNA from human nucleated cells.
        Nucleic Acids Res. 1988; 16: 1215
        • Day I.N
        • Humphries S.E
        Electrophoresis for genotyping: microtiter array diagonal gel electrophoresis on horizontal polyacrylamide gels, hydrolink, or agarose.
        Anal. Biochem. 1994; 222: 389-395
        • Chakravarti A
        • Buetow K.H
        • Antonarakis S.E
        • Waber P.G
        • Boehm C.D
        • Kazazian H.H
        Nonuniform recombination within the human β-globin gene cluster.
        Am. J. Hum. Genet. 1984; 36: 1239-1258
        • Bates C.J
        • Mansoor M.A
        • van der Pols J
        • Prentice A
        • Cole T.J
        • Finch S
        Plasma total homocysteine in a representative sample of 972 British men and women aged 65 and over.
        Eur. J. Clin. Nutr. 1997; 51: 691-697
        • Malinow M.R
        • Ducimetiere P
        • Luc G
        • Evans A.E
        • Arveiler D
        • Cambien F
        • Upson B.M
        Plasma homocyst(e)ine levels and graded risk for myocardial infarction: findings in two populations at contrasting risk for coronary heart disease.
        Atherosclerosis. 1996; 126: 27-34
        • Ministry of Agriculture
        Fisheries and food.
        in: National Food Survey. H.M.S.O, London1994: 1996
        • Stampfer M.J
        • Malinow M.R
        • Willett W.C
        • et al.
        A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians.
        J. Am. Med. Assoc. 1992; 268: 877-881
        • Nygard O
        • Vollset S.E
        • Refsum H
        • et al.
        Total plasma homocysteine and cardiovascular risk profile. The Hordaland homocysteine study.
        J. Am. Med. Assoc. 1995; 274: 1526-1533
        • Sacchi E
        • Tagliabue L
        • Duca F
        • Mannucci P.M
        High frequency of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in Northern Italy.
        Thromb. Haemost. 1997; 78: 963-964
        • Schwartz S.M
        • Siscovick D.S
        • Malinow M.R
        • 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: 412-417
        • van der Mooren M.J
        • Demacker P.N
        • Blom H.J
        • de Rijke Y.B
        • Rolland R
        The effect of sequential three-monthly hormone replacement therapy on several cardiovascular risk estimators in postmenopausal women.
        Fertil. Steril. 1997; 67: 67-73
        • Mijatovic V
        • Netelenbos C
        • van der Mooren M.J
        • de Valk-de Roo G.W
        • Jakobs C
        • Kenemans P
        Randomized, double-blind, placebo-controlled study of the effects of raloxifene and conjugated equine estrogen on plasma homocysteine levels in healthy postmenopausal women.
        Fertil. Steril. 1998; 70: 1085-1089
        • Brown C.A
        • McKinney K.Q
        • Young K.B
        • Norton H.J
        The C677T methylenetetrahydrofolate reductase polymorphism influences the homocysteine-lowering effect of hormone replacement therapy.
        Mol. Genet. Metab. 1999; 67: 43-48
        • Boers G.H
        • Smals A.G
        • Trijbels F.J
        • Leermakers A.I
        • Kloppenborg P.W
        Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years.
        J. Clin. Invest. 1983; 72: 1971-1976
        • Andersson A
        • Brattstrom L
        • Israelsson B
        • Isaksson A
        • Hamfelt A
        • Hultberg B
        Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status.
        Eur. J. Clin. Invest. 1992; 22: 79-87