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

DL Harmon, JV Woodside, JWG Yarnell, D McMaster, IS Young, EE McCrum, KF Gey, AS Whitehead, AE Evans

    Research output: Contribution to journalArticle

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    Abstract

    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-beta-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.
    LanguageEnglish
    Pages571-577
    JournalQJM - Monthly Journal of the Association of Physicians
    Volume89
    Issue number8
    Publication statusPublished - Aug 1996

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    Methylenetetrahydrofolate Reductase (NADPH2)
    Hyperhomocysteinemia
    Folic Acid
    Homocysteine
    Genotype
    Mutation
    Neural Tube Defects
    Vascular Diseases
    Cystathionine beta-Synthase
    Population
    Loss of Heterozygosity
    Homozygote
    Vitamin B 12
    Dietary Supplements
    Serum
    Vitamins
    Genes
    Phenotype

    Cite this

    Harmon, DL., Woodside, JV., Yarnell, JWG., McMaster, D., Young, IS., McCrum, EE., ... Evans, AE. (1996). The common `thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. QJM - Monthly Journal of the Association of Physicians, 89(8), 571-577.
    Harmon, DL ; Woodside, JV ; Yarnell, JWG ; McMaster, D ; Young, IS ; McCrum, EE ; Gey, KF ; Whitehead, AS ; Evans, AE. / The common `thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. In: QJM - Monthly Journal of the Association of Physicians. 1996 ; Vol. 89, No. 8. pp. 571-577.
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    abstract = "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-beta-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.",
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    Harmon, DL, Woodside, JV, Yarnell, JWG, McMaster, D, Young, IS, McCrum, EE, Gey, KF, Whitehead, AS & Evans, AE 1996, 'The common `thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia', QJM - Monthly Journal of the Association of Physicians, vol. 89, no. 8, pp. 571-577.

    The common `thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. / Harmon, DL; Woodside, JV; Yarnell, JWG; McMaster, D; Young, IS; McCrum, EE; Gey, KF; Whitehead, AS; Evans, AE.

    In: QJM - Monthly Journal of the Association of Physicians, Vol. 89, No. 8, 08.1996, p. 571-577.

    Research output: Contribution to journalArticle

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    T1 - The common `thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia

    AU - Harmon, DL

    AU - Woodside, JV

    AU - Yarnell, JWG

    AU - McMaster, D

    AU - Young, IS

    AU - McCrum, EE

    AU - Gey, KF

    AU - Whitehead, AS

    AU - Evans, AE

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    N2 - 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-beta-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.

    AB - 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-beta-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.

    M3 - Article

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    T2 - QJM: An International Journal of Medicine

    JF - QJM: An International Journal of Medicine

    SN - 1460-2725

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    ER -