Ludwig E, Corneli P S, Anderson J L, Marshall H W, Lalouel J M, Ward R H
Department of Human Genetics, University of Utah, Salt Lake City 84112, USA.
Circulation. 1995 Apr 15;91(8):2120-4. doi: 10.1161/01.cir.91.8.2120.
Although both genetic and nongenetic factors contribute to the pathogenesis of coronary artery disease, the identification of specific genetic lesions has lagged behind the identification of critical environmental risk factors. A reported association between myocardial infarction (MI) and the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in European men suggests a critical role for this genomic region. However, the generality of this association remains to be determined. It also is not clear at what stage in disease progression the association with the ACE I/D polymorphism becomes important.
We evaluated the ACE I/D polymorphism in patients who had undergone coronary angiography (402 men and 295 women) and in 203 representative control subjects. After polymerase chain reaction amplification, genotypes were determined by agarose gel sizing and by hybridization with allele-specific oligonucleotides. After patients were categorized by the degree of coronary artery stenosis and the occurrence of an MI, the distribution of ACE I/D genotypes was evaluated by log linear analysis. Patients were genetically representative of the regional population, and patients with > 60% stenosis of their coronary arteries had the same distribution of ACE I/D genotypes as did patients with < 10% stenosis. However, among patients with stenosis, the occurrence of an MI was significantly associated with the D allele in all patients (odds ratio [OR], 1.59; P = .002) and in men alone (OR, 1.63; P = .006). The lack of significance in women (OR, 1.40; P = .263) is probably due to the fact that only 36 women in the present study had experienced an MI. Furthermore, the association between MI and the ACE I/D polymorphism was independent of blood pressure, smoking habits, and body mass index.
Segregation of the ACE I/D polymorphism is a pervasive genetic risk factor for MI in whites but has no evident effect on the events leading to stenosis of the coronary arteries. This suggests that risk of MI is influenced by two independent processes--atherogenesis that leads to coronary stenosis followed by conversion to MI. The renin-angiotensin system appears to confer significant risk of infarction by influencing the conversion to MI but has no apparent effect on the development of atherostenosis.
尽管遗传因素和非遗传因素都对冠状动脉疾病的发病机制有影响，但特定遗传损伤的识别滞后于关键环境危险因素的识别。一项关于欧洲男性心肌梗死（MI）与血管紧张素转换酶（ACE）基因插入/缺失（I/D）多态性之间关联的报告表明该基因组区域起关键作用。然而，这种关联的普遍性仍有待确定。同样不清楚与ACE I/D多态性的关联在疾病进展的哪个阶段变得重要。
我们评估了接受冠状动脉造影的患者（402名男性和295名女性）以及203名代表性对照受试者的ACE I/D多态性。经聚合酶链反应扩增后，通过琼脂糖凝胶大小测定和与等位基因特异性寡核苷酸杂交来确定基因型。在根据冠状动脉狭窄程度和MI的发生情况对患者进行分类后，通过对数线性分析评估ACE I/D基因型的分布。患者在遗传上代表该地区人群，冠状动脉狭窄>60%的患者与狭窄<10%的患者具有相同的ACE I/D基因型分布。然而，在狭窄患者中，MI的发生在所有患者中（优势比[OR]，1.59；P = 0.002）以及仅在男性中（OR，1.63；P = 0.006）与D等位基因显著相关。女性中缺乏显著性（OR，1.40；P = 0.263）可能是因为本研究中只有36名女性经历过MI。此外，MI与ACE I/D多态性之间的关联独立于血压、吸烟习惯和体重指数。
ACE I/D多态性的分离是白人中MI普遍存在的遗传危险因素，但对导致冠状动脉狭窄的事件没有明显影响。这表明MI的风险受两个独立过程影响——导致冠状动脉狭窄随后转变为MI的动脉粥样硬化形成过程。肾素 - 血管紧张素系统似乎通过影响向MI的转变赋予显著的梗死风险，但对动脉粥样硬化狭窄的发展没有明显影响。
