Background: Endothelial nitric oxide synthase (eNOS) could be a candidate gene for coronary artery disease (CAD). This study investigated the relationship of the eNOS Glu 298 3 Asp and T 786 3 C polymorphisms with the presence and severity of CAD in the Italian population. Methods: We enrolled 415 unrelated individuals who underwent coronary angiography. The severity of CAD was expressed by means of the Duke score. The eNOS Glu 298 3 Asp and T 786 3 C variants were analyzed by PCR. Results: There was significant linkage disequilibrium between the two eNOS polymorphisms (P <0.0001). Both variants were significantly associated with the occurrence and severity of CAD (P ‫؍‬ 0.01 and 0.004 for Glu 298 3 Asp and T 786 3 C, respectively). The risk of CAD was increased among individuals homozygous for the C allele of the T 786 3 C polymorphism compared with individuals homozygous for the T allele (odds ratio ‫؍‬ 2.5; P <0.01) and was independent of the other common risk factors (P ‫؍‬ 0.04). Moreover, individuals with both the Asp/Asp genotype of the Glu 298 3 Asp polymorphism and at least one C allele of the T 786 3 C variant in the promoter region of the eNOS gene had an increased risk of CAD (odds ratio ‫؍‬ 4.0; P <0.001) and a significantly higher mean Duke score (26.2 ؎ 2.9 vs 45.2 ؎ 3.7; P ‫؍‬ 0.002) compared with individuals with the TT genotype and the Glu allele. Conclusions:The present study provides evidence that the Glu 298 3 Asp and T 786 3 C polymorphisms of the eNOS gene are associated with the presence and sever-

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These data indicate an overall elevation of oxidative DNA damage in CAD patients correlated with the severity of the disease and some atherogenic risk factors, suggesting a possible role of oxidative genetic damage in the pathogenesis of atherosclerosis.

Epidemiological studies indicated a role for polymorphisms in genes of folate and homocysteine (Hcy) metabolism in the etiology of neurodegenerative disease, congenital defects and coronary artery disease (CAD). This study investigated the effect of several polymorphisms [C677 T, A1298C of methylenetetrahydrofolate reductase (MTHFR) and A66G of methionine synthase reductase (MTRR) genes] on Hcy levels and DNA damage in 68 patients who underwent coronary angiography. Plasma Hcy concentrations were higher in patients with multivessel disease with respect to monovessel disease and no-CAD patients (19.472.6 vs 11.671.2 and 13.771.4 lmol/l, respectively; P ¼ 0.03). 677TT patients had higher Hcy levels than those with 677CC or 677CT genotypes (26.274.3 vs 13.171.4 and 13.071.4 lmol/l, respectively; P ¼ 0.0006). No significant associations were found between A1298C and A66G polymorphisms and plasma Hcy levels. Among patients with 677CC genotype, 66GG individuals tended to have higher levels of Hcy than 66AA homozygotes (14.571.9 vs 8.970.7 lmol/l, P ¼ 0.06). Multivessel disease patients showed an increased frequency of DNA damage, measured by the micronucleus (MN) frequency, as compared to monovessel disease and no-CAD subjects (12.571.1 vs 8.570.8 and 8.270.9, respectively; P ¼ 0.006). The MN were positively correlated with Hcy levels (r ¼ 0.33, P ¼ 0.006) and were significantly higher in subjects with the 677TT genotype compared with the 677CC or 677CT genotypes (14.472.0 vs 8.871.2 and 9.570.7, respectively; P ¼ 0.006). A1298C and A66G polymorphisms had no effect on MN frequency. However, among 677TT patients, 66GG subjects tended to have higher levels of MN than those 66AG and 66AA (18.273.6 vs 13.874.0 and 10.371.7, respectively; P ¼ NS). Our results indicate that genetic instability may be associated with increased risk for multiple Hcy-related diseases.