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

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.

Influence of the cystathionine β-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations

“…5,11 The study was approved by the Research Ethics Committee of the Faculty of Medicine, The Queen's University of Belfast. All subjects provided written informed consent before participation.…”

“…4 MTHFR 677TT homozygotes are more likely than those with the CT or CC genotypes to have hyperhomocysteinemia, especially under low folate conditions. 5,6 The CBS 844ins68 allele contains an insertion of 68 bp in exon 8. First reported in a homocystinuric patient by Sebastio et al, 7 this polymorphism was initially thought to mandate the use of an insertion-associated premature stop codon in the CBS mRNA leading to the translation of a truncated inactive enzyme.…”

Evidence for sex differences in the determinants of homocysteine concentrations

“…The MTHFR 677TT genotype confers a significant risk of hyperhomocysteinemia that is most pronounced in individuals with low folate [15,16] or low riboflavin [17] status. Interestingly, the MTHFR 677C>T polymorphism appears to have a sex-specific effect on homocysteine [18].…”

Hyperhomocysteinaemia in a young woman presenting with stroke, associated with methylene tetrahydrofolate reductase C677T homozygosity

“…This agrees with a previous statement that many homozygous individuals may have normal homocysteine concentrations but in the presence of suboptimal folate intake may develop hyperhomocysteinaemia. 6 At a high folate intake there is no association with the polymorphism and risk of CHD. 8 Had this family not been screened, we would have missed one case with moderate hyperhomocysteinaemia which potentially could have caused thrombosis.…”