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The common ‘thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia

Harmon, D.L. ; Woodside, J.V. ; Yarnell, J.W.G. ; McMaster, D. ; Young, I.S. ; McCrum, E.E. ; Gey, K.F. ; Whitehead, A.S. ; Evans, A.E.

In: QJM: An International Journal of Medicine, 1996, vol. 89, no. 8, p. 571-578

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    Titre
    • The common ‘thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia
    Auteur
    • Harmon, D.L.. Department of Genetics and Biotechnology Institute, Trinity College Dublin 2, Ireland
    • Woodside, J.V.. Department of Epidemiology and Public Health, The Queen's University of Belfast Northern Ireland
    • Yarnell, J.W.G.. Department of Epidemiology and Public Health, The Queen's University of Belfast Northern Ireland
    • McMaster, D.. Department of Medicine, The Queen's University of Belfast Northern Ireland
    • Young, I.S.. Department of Clinical Biochemistry, The Queen's University of Belfast Northern Ireland
    • McCrum, E.E.. Department of Epidemiology and Public Health, The Queen's University of Belfast Northern Ireland
    • Gey, K.F.. Vitamin Unit, Department of Biochemistry and Molecular Biology, University of Berne Switzerland
    • Whitehead, A.S.. Department of Genetics and Biotechnology Institute, Trinity College Dublin 2, Ireland
    • Evans, A.E.. Department of Epidemiology and Public Health, The Queen's University of Belfast Northern Ireland
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • QJM: An International Journal of Medicine, 1996, vol. 89, no. 8, p. 571-578. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:296829
    Summary
    Mild hyperhomocysteinaemia is a major risk factor for vascular disease and neural tube defects (NTDs), conferring an approximately three-fold relative risk for each condition. It has several possible causes: heterozygosity for rare loss of function mutations in the genes for 5,10-methylene tetrahydrofolate reductase (MTHFR) or cystathionine-β-synthase (CBS); dietary insufficiency of vitamin co-factors B6, B12 or folates; or homozygosity for a common ‘thermolabile' mutation in the MTHFR gene which has also been associated with vascular disease and NTDs. We quantified the contribution of the thermolabile mutation to the hyperhomocysteinaemic phenotype in a working male population (625 individuals). Serum folate and vitamin B12 concentrations were also measured and their relationship with homocysteine status and MTHFR genotype assessed. The homozygous thermolabile genotype occurred in 48.4, 35.5, and 23.4% of the top 5,10, and 20% of individuals (respectively) ranked by plasma homocysteine levels, compared with a frequency of 11.5% in the study population as a whole, establishing that the mutation is a major determinant of homocysteine levels at the upper end of the range. Serum folate concentrations also varied with genotype, being lowest in thermolabile homozygotes. The MTHFR thermolabile genotype should be considered when population studies are designed to determine the effective homocysteine-lowering dose of dietary folate supplements, and when prophylactic doses of folate are recommended for individuals