Alvarez R, González P, Batalla A, Reguero J R, Iglesias-Cubero G, Hevia S, Cortina A, Merino E, González I, Alvarez V, Coto E
Laboratorio de Genética Molecular-Instituto de Investigación Nefrológica, Hospital Central de Asturias, Oviedo, Spain.
Nitric Oxide. 2001 Aug;5(4):343-8. doi: 10.1006/niox.2001.0351.
DNA polymorphisms at the endothelium constitutive nitric oxide synthase gene (NOS3) have been linked to the risk of developing coronary artery disease (CAD). In vitro, a polymorphism in the 5' region of the NOS3 gene (-786 T/C) influences promoter activity. This polymorphism has been associated with coronary spasms among Japanese. The genetic variation at the angiotensin-converting enzyme (ACE) is associated with plasma ACE activities and has also been linked with susceptibility to cardiovascular disease. Our objective was to determine if DNA polymorphisms in the NOS3 and ACE genes were associated with early CAD. We analyzed the -786 T/C polymorphism in the 5' flanking region and the 27-bp repeat polymorphism in NOS3 intron 4, as well as the ACE-I/D polymorphism. A total of 170 male smokers (CAD patients) younger than 50 years and 300 male smokers (healthy controls) were genotyped. Frequencies were compared by the chi(2) test, and odds ratios (ORs) and their 95% confidence intervals (CI) were also calculated. Only the -786 T/C polymorphism in the 5' flanking region of the NOS3 gene was significantly associated with early CAD in our population. The frequency of the CC genotype was significantly increased (P = 0.039) in patients compared to controls (OR = 1.67; 95% CI = 1.01, 2.72). We found a synergistic effect between the NOS3-CC and the ACE-DD genotypes in the risk of developing early CAD. The frequency of CC + DD was significantly increased among patients (P = 0.002). Thus, those with a NOS3-CC and an ACE-DD genotype would have a significantly increased risk of suffering an early episode of coronary artery disease (OR = 2.82; 95% CI = 1.40, 5.70). Although based on a limited number of patients, our work suggests that individuals who are NOS3-CC + ACE-DD are at a higher risk for early CAD, probably as a consequence of increased endothelial dysfunction.
内皮型一氧化氮合酶基因（NOS3）的DNA多态性与冠状动脉疾病（CAD）的发病风险相关。在体外实验中，NOS3基因5'区域的一个多态性位点（-786 T/C）会影响启动子活性。这种多态性与日本人的冠状动脉痉挛有关。血管紧张素转换酶（ACE）的基因变异与血浆ACE活性相关，也与心血管疾病易感性有关。我们的目的是确定NOS3和ACE基因的DNA多态性是否与早期CAD相关。我们分析了NOS3基因5'侧翼区域的-786 T/C多态性、NOS3基因内含子4中的27 bp重复多态性以及ACE的I/D多态性。对170名年龄小于50岁的男性吸烟者（CAD患者）和300名男性吸烟者（健康对照）进行了基因分型。通过卡方检验比较频率，并计算优势比（OR）及其95%置信区间（CI）。在我们的研究人群中，只有NOS3基因5'侧翼区域的-786 T/C多态性与早期CAD显著相关。与对照组相比，患者中CC基因型的频率显著增加（P = 0.039）（OR = 1.67；95% CI = 1.01，2.72）。我们发现NOS3-CC和ACE-DD基因型在早期CAD发病风险中存在协同作用。患者中CC + DD的频率显著增加（P = 0.002）。因此，具有NOS3-CC和ACE-DD基因型的个体患早期冠状动脉疾病的风险会显著增加（OR = 2.82；95% CI = 1.40，5.70）。尽管基于有限数量的患者，但我们的研究表明，NOS3-CC + ACE-DD个体患早期CAD的风险更高，这可能是内皮功能障碍增加的结果。
