RESUMEN
BACKGROUND: Hyperhomocyteinemia (HHcy) is a risk factor for coronary artery disease (CAD), and methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) polymorphisms may contribute to plasma total homocysteine (tHcy) variation. We investigated the association of polymorphisms 1298A-->C in the MTHFR gene, 2756A-->G in the MTR gene, and 66A-->G in the MTRR gene with tHcy levels and with CAD in patients undergoing coronary angiography. METHODS: CAD patients (n=151) and control subjects (n=79) were compared regarding the prevalence of the polymorphisms, risk factors, and biochemical parameters. RESULTS: The mean tHcy concentration was significantly higher in CAD patients than in control subjects (P<0.001). HHcy (tHcy>/=15 mumol/l) conferred an OR of CAD of 4.1 (95% CI 2.2-7.5, P<0.001). In both cases and controls, smokers had a higher tHcy level than non-smokers and demonstrated a markedly increased risk for CAD (OR=2.5, 95% CI 1.7-3.3, P<0.001). The allele frequencies of the MTHFR 1298A-->C, MTR 2756A-->G, and MTRR 66A-->G mutations were 36.7%, 15.7%, and 36.6%, respectively. The 1298C allele frequency was significantly higher in the CAD group than in controls (P<0.05) and showed a significant association with CAD in heterozygote carriers. There was no statistically significant difference between cases and controls in the frequencies of the A2756G alleles/genotypes in the MTR gene and of the A66G alleles/genotypes in the MTRR gene. The contributions to tHcy levels of the three common mutations were statistically significant. The heterozygosity of the MTHFR 1298AC genotype, MTR 2756G allele, and MTRR 66G allele yielded an OR of 3.4, 2.0, and 2.1, respectively, for having HHcy. CONCLUSION: We suggest that HHcy confers a risk for CAD, and smokers with tHcy are at a greatly increased risk. Our finding supports an important role of the MTHFR gene in CAD and provides evidence of polygenic regulation of tHcy.
RESUMEN
Increased plasma total homocysteine (tHcy) levels have been shown to be a risk factor for coronary artery disease (CAD). The common methylenetetrahydrofolate reductase C677T (MTHFR C677T) polymorphism has been reported to be a strong predictor of mild hyperhomocysteinaemia (HHcy). We assessed whether this mutation was associated with increased risk of CAD and plasma levels of tHcy. We also evaluated interactions between this polymorphism, mild elevated tHcy levels and conventional risk factors of CAD. Method. Using PCR-RFLP analysis, we studied the frequency of the C677T genotypes and its effect on CAD and on tHcy concentrations in 400 subjects without and with CAD angiographically confirmed. There were 210 subjects with CAD and 190 subjects without CAD. Results. The frequencies of the C677T genotypes were 53% (59.5% in controls versus 48.1% in cases), 34.8% (32.1 in controls versus 37.1 in cases), and 11.8% (8.4% in controls versus 14.8% in cases), respectively, for 677CC, 677CT, and 677TT. The genotype frequencies were significantly different between case and control groups (P < .05). The 677T allele enhances the risk of CAD associated to HHcy (P < .01). In multivariate analysis models, MTHFR C677T polymorphism effect on CAD was masked by other risk factors. HHcy was only and independently influenced by MTHFR polymorphism and smoking habits, and it is a strong predictor of CAD independently of conventional risk factors. Conclusion. Our data suggest that HHcy is strongly and independently associated to CAD risk increase; and MTHFR C677T polymorphism and smoking habits were the main predictors of tHcy levels. The CAD risk increase is mainly associated with mild HHcy in 677TT, whereas in 677CT and 677CC it is mainly associated with the conventional risk factors.
RESUMEN
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.
