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

Mild hyperhomocysteinaemia is a major risk factor for vascular disease andneural tube defects (NTDs), conferring an approximately three-fold relativerisk for each condition. It has several possible causes: heterozygosity forrare loss of function mutations in the genes for 5,10-methylenetetrahydrofolate reductase (MTHFR) or cystathionine-&bgr;-synthase(CBS); dietary insufficiency of vitamin co-factors B6, B12 or folates; orhomozygosity for a common 'thermolabile' mutation in the MTHFR gene whichhas also been associated with vascular disease and NTDs. We quantified thecontribution of the thermolabile mutation to the hyperhomocysteinaemicphenotype in a working male population (625 individuals). Serum folate andvitamin B12 concentrations were also measured and their relationship withhomocysteine status and MTHFR genotype assessed. The homozygousthermolabile genotype occurred in 48.4, 35.5, and 23.4% for the top 5, 10and 20% of individuals repectively) ranked by plasma homocysteine levels,compared with a frequency of 11.5% in the study population as a wholeestablishing that the mutation is a major determinant of homocystein levelsat the upper end of the range. Serum folate concentrations also varied withgenotype, being lowest in thermolabile homozygotes. The MTHFR thermolabilegenotype should be considered when population studies are designed todetermine the effective homocysteine-lowering dose of dietary folatesupplements, and when prophylactic doses of folate are recommended forindividuals.