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 and neural tube defects (NTDs), conferring an approximately three-fol d relative risk for each condition. It has several possible causes: he terozygosity for rare loss of function mutations in the genes for 5,10 -methylene tetrahydrofolate reductase (MTHFR) or cystathionine-beta-sy nthase (CBS); dietary insufficiency of vitamin co-factors B6, B12 or f olates; or homozygosity for a common 'thermolabile' mutation in the MT HFR gene which has also been associated with vascular disease and NTDs . We quantified the contribution of the thermolabile mutation to the h yperhomocysteinaemic phenotype in a working male population (625 indiv iduals). Serum folate and vitamin B12 concentrations were also measure d and their relationship with homocysteine status and MTHFR genotype a ssessed. The homozygous thermolabile genotype occurred in 48.4, 35.5, and 23.4% of the top 5, 10, and 20% of individuals (respectively) rank ed by plasma homocysteine levels, compared with a frequency of 11.5% i n the study population as a whole, establishing that the mutation is a major determinant of homocysteine levels at the upper end of the rang e. Serum folate concentrations also varied with genotype, being lowest in thermolabile homozygotes. The MTHFR thermolabile genotype should b e considered when population studies are designed to determine the eff ective homocysteine-lowering dose of dietary folate supplements, and w hen prophylactic doses of folate are recommended for individuals.