Methylene tetrahydrofolate reductase genotype and the risk and extent of coronary artery disease in a population with low plasma folate

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Abstract
OBJECTIVE To determine the effects of the thermolabile methylene tetrahydrofolate reductase (MTHFR) mutation on the presence and extent of coronary atherosclerosis in a population with low plasma folate. METHODS 242 consecutive patients undergoing coronary angiography were prospectively evaluated for conventional risk factors, plasma homocysteine, vitamin B-12, and folate, and MTHFR genotype. The severity of coronary atherosclerosis was determined by the Leaman score. RESULTS Mean (SD) plasma homocysteine was 15.6 (10) μmol/l in controls and 18.5 (11) μmol/l in patients with coronary artery disease (p > 0.05). Plasma homocysteine concentrations above 15 μmol/l were a risk factor for coronary artery disease (p = 0.03, risk ratio 2.1, 95% confidence interval (CI) 1.07 to 4.4). Homocysteine remained an independent risk factor on multivariate analysis when conventional risk factors were taken into account (p = 0.04). Homocysteine concentrations above 15 μmol/l were correlated with the extent of atherosclerosis (p = 0.04, risk ratio 3.2, 95% CI 1.3 to 8.2). Homocysteine had no effect on other lipid variables (p > 0.05). Plasma folate was 15.8 (7.2) nmol/l in controls and 11.5 (2.9) nmol/l in patients with coronary artery disease. Plasma folate concentrations below 12.9 nmol/l (5.7 ng/ml) conferred a risk for coronary artery disease (p = 0.03, risk ratio 2.42, 95% CI 1.05 to 5.59). When the MTHFR genotype was determined, the TT genotype was present in 7.4% of patients and 5.2% of controls (p > 0.05). The prevalence of alleles was within the Hardy–Weinberg equilibrium (TT 7, CT 40, CC 53, χ2 = 2.3, p = 0.3). The highest homocysteine concentrations were found in patients with the TT genotype and folate below the median of the population (p = 0.01). The extent of coronary atherosclerosis judged by the Leaman score was significantly higher in patients with the TT genotype (p = 0.03). CONCLUSIONS Plasma homocysteine over 15 μmol/l was a significant risk factor for the presence and extent of coronary artery disease. The mean plasma folate of the population was low and correlated negatively with homocysteine. Although TT genotype was not an independent predictor of coronary artery disease, it was an important predictor of the extent of coronary atherosclerosis and plasma homocysteine, especially in the presence of plasma folate values below the median of the population. These findings may have important implications for folate replacement in patients with the TT genotype.