Methylenetetrahydrofolate reductase genotypes and predisposition to atherothrombotic disease - Evidence that all three MTHFR C677T genotypes confer different levels of risk

Aims Elevated plasma homocysteine is an independent risk factor for atherot hrombotic disease. Individuals homozygous for the methylenetetrahydrofolate reductase (MTHFR) 677C allele exclusively accumulate 5-methyltetrahydrofol ate. the methyl donor for homocysteine remethylation. in their red blood ce lls. this contrasts with 677 TT homozygotes who also accumulate significant levels of non-methylated folate derivatives. Those with the MTHFR 677 TT. CT and CC genotypes may therefore differ qualitatively with respect to fola te utilization and hence their capacity to remethylate homocysteine. This s tudy was consequently designed to establish whether all three genotypes con fer different levels of atherothrombotic risk. Methods and Results The risk of atherothrombotic disease conferred by the M THFR 677 CT and 677 CC genotypes was assessed using a 'restricted' meta-ana lysis approach applied to subjects from the first ten studies reporting a s ignificantly increased risk conferred by the 677 TT genotype. The defined r isk of the TT genotype in each of these ten studies was judged by us to den ote 'genetic vulnerability' in the populations from which subjects were dra wn. After proportional adjustment for the greater number of case TT homozyg otes, the CT and CC frequencies observed in cases were compared with expect ations based on the frequencies of these genotypes in controls. The observe d CT frequency among cases was higher than expected in eight of the ten stu dies. In the meta-analysis, which included 1857 cases and 2942 controls, 84 7 (45.6%) cases, instead of the 777 (41.8%) expected, had the MTHFR CT geno type (P = 0.010). Conclusions Our findings suggest that the three MTHFR C677T genotypes confe r different levels of atherothrombotic risk in 'genetically vulnerable' pop ulations: CT heterozygotes have an elevated risk over CC homozygotes. One e xplanation is that the CT genotype actively confers atherothrombotic risk. An alternative interpretation however, for which a biologically plausible m echanism is proposed, is that CC is a protective genotype. (Eur Heart J 200 1; 22: 294-299, doi:10.1053/euhj.2000.2239) (C) 2001 The European Society o f Cardiology.