Investigations of a common genetic variant in betaine-homocysteine methyltransferase (BHMT) in coronary artery disease

Atherosclerosis. 2003 Apr;167(2):205-14. doi: 10.1016/s0021-9150(03)00010-8.


Hyperhomocysteinemia, a risk factor for cardiovascular disease, can be caused by genetic mutations in enzymes of homocysteine metabolism. Homocysteine remethylation to methionine is catalyzed by folate-dependent methionine synthase, or by betaine-homocysteine methyltransferase (BHMT), which utilizes betaine as the methyl donor. Since genetic variants in folate-dependent remethylation have been reported to increase risk for cardiovascular disease and other common disorders, we screened BHMT for sequence changes that might alter risk for coronary artery disease (CAD). A variant in exon 6-R239Q-was identified. The frequency of this change was examined in 504 individuals who had undergone coronary angiography and were stratified into controls (those with no or mild disease) and cases (those with significant [>50% reduction in luminal diameter stenosis] 1-, 2-, 3-vessel disease). Although this variant did not affect plasma homocysteine, the QQ genotype was present in higher frequency in those with no or mild disease, compared with those with significant disease (11 vs. 6%), suggesting that it may decrease risk of CAD; a statistically-significant decrease was seen in the older subjects (13 vs. 7%). Multivariate analysis for the entire group revealed an odds ratio of 0.48 (95% CI: 0.21-1.06) for the QQ genotype; this association was similar in the younger (OR=0.36; 95% CI: 0.09-1.41) and older subjects (OR=0.42; 95% CI: 0.15-1.18). Our study suggests that the Q allele of the R239Q mutation may decrease the risk of CAD and that this variant warrants additional investigation of its relationship with the development of CAD as well as other homocysteine-dependent disorders.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Base Sequence
  • Betaine-Homocysteine S-Methyltransferase
  • Cohort Studies
  • Confidence Intervals
  • Coronary Angiography
  • Coronary Artery Disease / diagnostic imaging
  • Coronary Artery Disease / epidemiology
  • Coronary Artery Disease / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Humans
  • Hyperhomocysteinemia / epidemiology
  • Hyperhomocysteinemia / genetics*
  • Male
  • Methyltransferases / genetics*
  • Middle Aged
  • Molecular Sequence Data
  • Multivariate Analysis
  • Mutation
  • Odds Ratio
  • Polymorphism, Genetic*
  • Polymorphism, Single-Stranded Conformational
  • Probability
  • Risk Factors
  • Sensitivity and Specificity


  • BHMT2 protein, human
  • Methyltransferases
  • BHMT protein, human
  • Betaine-Homocysteine S-Methyltransferase