Premature atherosclerosis is not systematic in phytosterolemic patients: severe hypercholesterolemia as a confounding factor in five subjects.

OBJECTIVE: Phytosterolemia is a rare autosomal recessive disorder characterized by dramatically elevated circulating levels of plant sterols (PS). Phytosterolemia is believed to be responsible for severe premature atherosclerosis. The clinical, biological and molecular genetic features of 5 patients with phytosterolemia and transient severe hypercholesterolemia challenge this hypothesis. METHODS: Our patients were referred for suspected homozygous familial hypercholesterolemia. Despite the phenotype, this diagnosis was invalidated and phytosterolemia was confirmed by the identification of mutations in the ABCG5/ABCG8 transporter complex. Plasma PS were analyzed with a mass spectrometric-gas chromatographic procedure. Vascular status was assessed with carotid ultrasonography and completed (for 4 of the 5 patients) with femoral ultrasonography; additional examinations of cardiovascular status included a stress test, determination of coronary calcium score, echocardiography, non-invasive assessment of endothelium-dependent dilatation and coronarography. RESULTS: The 5 patients displayed markedly elevated levels of both ß-sitosterol and campesterol (15-30 fold higher than normal values). However, none displayed significant signs of infraclinical premature atherosclerosis (respectively at the ages of 32, 27, 29, 11 and 11 years). All patients were characterized by very high levels of total (>450 mg/dl) and LDL-cholesterol (>350 mg/dl) at diagnosis which decreased markedly on dietary intervention alone. Treatment with cholestyramine or Ezetimibe ± atorvastatin normalized cholesterol levels, although plasma PS concentrations remained elevated. CONCLUSION: The clinical and biological characteristics of our patients, considered together with reports of cases which equally lack CVD, support the contention that the premature atherosclerosis associated with phytosterolemia in some patients may be due at least in part to mechanisms independent of elevated circulating phytosterol levels.

Influence of methionine synthase (A2756G) and methionine synthase reductase (A66G) polymorphisms on plasma homocysteine levels and relation to risk of coronary artery disease.

BACKGROUND: Elevated plasma total homocysteine (tHcy) is increasingly being recognized as a risk factor for coronary artery disease (CAD) and other defects. Recent genetic studies have characterized molecular determinants contributing to altered homocysteine metabolism. Our objectives were therefore to confirm the relationship of tHcy with CAD and to examine the importance of genetic influence on tHcy in the coronary angiograms and conventional cardiovascular risk factors recorded in 230 subjects. We also determined the genotype frequencies distribution of the A2756G transition of the B12-dependent methionine synthase (MTR) gene and the A66G mutation of the methionine synthase reductase (MTRR) gene. RESULTS: Patients with CAD (n=151) had significantly higher tHcy concentrations than control subjects (15.49 +/- 2.75 micromol/l vs. 11.21 +/- 3.54 micromol/l, P < 0.001). Hyperhomocysteinaemia (tHcy > or =15 micromol/l) was a risk factor for CAD [RR = 4.07, 95% CI: 2.21 - 7.47, P < 0.001]. The homocysteine concentrations were significantly different between smokers and non-smokers, at 15.63 +/- 3.10 vs. 12.45 +/- 3.84 micromol/l, P < 0.05. In addition, smokers with hyperhomocysteinaemia demonstrated a markedly increased risk of CAD (OR = 2.50, 95% CI: 1.67 - 3.32, P < 0.05) compared with non-smokers with normal homocysteine.The 2756G and the 66G allele contribute to a moderate increase in homocysteine levels (P = 0.008 and P = 0.007, respectively), but not to CAD (P > 0.05). Combined MTR and MTRR polymorphisms, the 2756AG + 66AG and the 2756AG + 66GG were the combined genotypes that were a significant risk factor for having hyperhomocysteinaemia (14.4 +/- 2.8 micromol/l, OR = 2.75, IC 95% = 1.21 - 6.24, P=0.016 and 17.9 +/- 4.1 micromol/l, OR = 6.28, IC 95% = 1.46 - 12.1, P = 0.021, respectively). Statistic analysis using the UniANOVA test shows that these two polymorphisms have an interactive effect circulating homocysteine levels (P < 0.05). CONCLUSION: Our data suggest that moderately elevated tHcy levels are prevalent in our population and are associated with an increased risk for CAD. This study provides evidence that the MTR A2756G and MTRR A66G polymorphisms significantly influence the circulating homocysteine concentration. In addition, the MTR and MTRR genes may interact to increase the risk for having hyperhomocysteinaemia.