Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases

Michael Y. Tsai, Barry G. Welge, Naomi Q. Hanson, Michelle K. Bignell, John Vessey, Kerry Schwichtenberg, Feng Yang, Faye E. Bullemer, Rhonda Rasmussen, Kevin J. Graham

Research output: Contribution to journalArticlepeer-review

103 Scopus citations


Elevated plasma homocysteine is increasingly being recognized as a risk factor for coronary artery disease (CAD). Although there is general agreement on the importance of micronutrients and genetic predisposition to elevated plasma homocysteine, the exact influence of the known prevalent mutations in genes which regulate homocysteine metabolism is hot clear. We studied 376 cases of individuals with premature CAD with respect to their fasting and post-methionine load (PML) total homocysteine (tHcy) concentrations. We also determined the presence or absence of the T833C and G919A mutations of the cystathionine-β-synthase (CBS) gene, the C677T mutation of the methylene tetrahydrofolate reductase (MTHFR) gene, and the A2756G transition of the B12 dependent methionine synthase (MS) gene. Our objectives were therefore both to confirm the relationship of plasma homocysteine with premature CAD and to examine the importance of genetic influence on both fasting and PML homocysteine. Approximately 32% of the CAD patients had fasting hyperhomocysteinemia and 16% had PML hyperhomocysteinemia. Of these, 8.5% had both forms of hyperhomocysteinemia (combined hyperhomocysteinemia). The T833C mutation in the CBS gene and the thermolabile C677T mutation in the MTHFR gene seem to play an important role in the subset of individuals with combined hyperhomocysteinemia. The A2756G transition in the MS gene is not associated with elevated plasma tHcy. Many cases (47%) of hyperhomocysteinemia are not associated with micronutrient deficiencies, impaired renal function, and/or currently known genetic mutations. Further work is needed to study whether unknown mutations, particularly those residing in the intronic sequences of the genes involved in homocysteine metabolism, other environmental factors, or interaction of gene, nutrient, and environmental factors may be the cause of currently unexplained cases of mild hyperhomocysteinemia.

Original languageEnglish (US)
Pages (from-to)163-170
Number of pages8
Issue number1
StatePublished - Mar 1999

Bibliographical note

Funding Information:
This study was supported in part by a grant from the Minnesota Medical Foundation of the University of Minnesota and by a grant from the American Heart Association, Minnesota Affiliate.


  • B vitamins
  • Cardiovascular diseases
  • Cystathionine β- synthase
  • Homocysteine
  • Methionine load
  • Methionine synthase
  • Methylenetetrahydrofolate reductase


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