Methylenetetrahydrofolate reductase gene C677T polymorphism, homocysteine, vitamin B12, and DNA damage in coronary artery disease

Elevated levels of plasma homocysteine (Hcy), a risk factor for coronary artery disease (CAD), can result from genetic errors, e.g., the methylenetetrahydrofolate reductase (MTHFR) polymorphism, or nutrional deficien- cies, e.g., in vitamin B12 and folate. The mechanism by which Hcy induces atherosclerosis is not fully understood. Recently, Hcy has also been observed to induce DNA damage. In this study, we have investigated whether DNA damage is related to the C677T variant in the MTHFR gene and to plasma levels of Hcy, B12, and folate in pa- tients with CAD. Patients (n=46) with angiographically proven CAD were studied by using the micronucleus (MN) test, an accepted method for evaluating genetic in- stability. TT patients had plasma Hcy levels higher than those with the CT or CC genotypes (27.8±5.2 vs 13.7±2.2 and 12.9±1.9 µmol/l, respectively; P=0.02). Patients with multi-vessel disease had higher plasma Hcy levels (11.6± 1.2, 22.0±4.7, 19.3±3.9 µmol/l for one-, two- and three- vessel disease, respectively; P=0.05). The MN index in- creased with the number of affected vessels (8.4±0.7, 11.1±2.0, 14.2±1.7 for one-, two-, and three-vessels dis- ease, respectively; P=0.02) and was significantly higher in subjects with the TT genotype compared with the CC or CT genotypes (15.7±2.4 vs 8.9±1.7 and 9.9±0.8; P= 0.02). The MN index was also correlated negatively with plasma B12 concentration (r=-0.343; P=0.019) and posi- tively with plasma Hcy (r=0.429, P=0.005). These data indicate that the MN index is associated with the severity of CAD and is related to the MTHFR polymorphism, sug- gesting an interesting link between coronary atherosclero- sis and genetic instability in humans.