Serum homocysteine, methylenetetrahydrofolate reductase gene polymorphism and cardiovascular disease in heterozygous familial hypercholesterolemia

Livia Pisciotta, Claudio Cortese, Agostino Gnasso, Laura Liberatoscioli, Anna Pastore, Liliana Mannucci, Concetta Irace, Giorgio Federici, Stefano Bertolini

Research output: Contribution to journalArticlepeer-review


Mild hyperhomocysteinemia is considered an important risk factor for vascular disease. A common polymorphism (677C → T) in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with a decreased enzyme activity and consequent higher circulating levels of homocysteine. We hypothesized that the serum levels of homocysteine and/or the MTHFR polymorphism could influence the risk for coronary artery disease (CAD) in patients with heterozygous familial hypercholesterolemia (FH), who are genetically prone to atherosclerosis. We determined the MTHFR genotype and fasting total serum homocysteine level in 249 adult patients (103 males and 146 females) with heterozygous FH. MTHFR polymorphism was a major determinant of serum homocysteine in adult FH of both sexes. The logistic regression analysis showed that in FH patients a high level of homocysteine (>12 μmol/l, corresponding to the upper quartile of serum distribution) was the most significant predictor of CAD (n = 99) in all the groups considered (all CAD, previous myocardial infarction, myocardial infarction plus angiographically confirmed CAD). The adjusted odds ratio (OR (95% CI)) for the homocysteine-associated risk of CAD (upper quartile versus lower quartiles) was 3.27 (1.60-6.62) in males and females considered together, 5.67 (1.50-21.3) in males and 2.78 (1.17-6.62) in females. LDL cholesterol (upper quartile versus lower quartiles) and hypertension were the other variables independently associated with CAD. In both sexes MTHFR polymorphism was not an independent predictor of CAD. Plasma concentration of serum homocysteine, but not MTHFR genotype, is associated with an increased risk of CAD in male and female patients with heterozygous FH.

Original languageEnglish
Pages (from-to)333-338
Number of pages6
Issue number2
Publication statusPublished - Apr 2005


  • Coronary artery disease
  • Familial hypercholesterolemia
  • Homocysteine
  • Methylenetetrahydrofolate reductase
  • Myocardial infarction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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