Fatini Cinzia, Sticchi Elena, Sofi Francesco, Said Abdihakim Abdullahi, Pratesi Giovanni, Pulli Raffaele, Pratesi Carlo, Abbate Rosanna
Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.
J Vasc Surg. 2009 Dec;50(6):1399-404. doi: 10.1016/j.jvs.2009.07.075. Epub 2009 Sep 26.
Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis. Apart from traditional cardiovascular risk factors, several novel biologic mediators and genetic predisposing factors appear relevant in determining the atherogenetic process leading to PAD. Genes encoding for renin angiotensin system (RAS) components have been proposed as candidate in atherosclerosis. This study investigated four polymorphisms in angiotensinogen (AGT), angiotensin converting enzyme (ACE), and angiotensin II receptor type 1 (AGTR1), genes of RAS, in both predicting PAD and modulating the severity of the disease.
The ACE I/D and -240A>T, AGT M235T, and AGTR1 1166A>C polymorphisms were analyzed in 281 PAD patients and in 485 controls comparable for age and sex.
The ACE D and -240T alleles both significantly influenced the predisposition to PAD. The ACE D, but not -240 T, allele remained associated with PAD after Bonferroni correction (P = .004) and adjustment for cardiovascular risk factors (P = .03). The ACE D allele influenced PAD predisposition with a dose-dependent effect (odds ratio for ACE ID vs II genotype, 1.77; P = .006; ACE DD vs II genotype, 2.15; P = .001). The haplotype reconstruction analysis for the ACE gene showed that the D/-240T haplotype significantly and independently influenced the predisposition to PAD (P = .02). In 190 PAD patients with no additional atherosclerotic localizations (isolated PAD), a significant association between ACE D and -240T alleles and PAD was observed. Only the ACE D allele remained associated with isolated PAD after Bonferroni correction (P = .02) and after adjustment for cardiovascular risk factors (P = .02). The haplotype reconstruction analysis for the ACE gene showed that the D/-240T, but not the D/-240A haplotype significantly influenced the predisposition to PAD (P = .0003). No influence of the polymorphisms analyzed on the severity of the disease, according to Rutherford categories, was found.
The present study contributes data to highlight the role of the ACED/-240T haplotype in predisposing to PAD, also in the absence of other atherosclerotic comorbidities.
外周动脉疾病（PAD）是全身动脉粥样硬化的常见表现。除了传统的心血管危险因素外，一些新的生物介质和遗传易感因素在导致PAD的动脉粥样硬化形成过程中似乎也具有相关性。编码肾素血管紧张素系统（RAS）成分的基因已被认为是动脉粥样硬化的候选基因。本研究调查了RAS基因中的血管紧张素原（AGT）、血管紧张素转换酶（ACE）和血管紧张素II 1型受体（AGTR1）的四种多态性，以预测PAD并调节疾病的严重程度。
对281例PAD患者和485例年龄和性别匹配的对照者进行ACE I/D和-240A>T、AGT M235T以及AGTR1 1166A>C多态性分析。
ACE D等位基因和-240T等位基因均显著影响PAD的易感性。经Bonferroni校正（P = .004）和心血管危险因素校正后（P = .03），ACE D等位基因而非-240T等位基因仍与PAD相关。ACE D等位基因对PAD易感性的影响呈剂量依赖性（ACE ID与II基因型的比值比为1.77；P = .006；ACE DD与II基因型的比值比为2.15；P = .001）。ACE基因的单倍型重建分析显示，D/-240T单倍型显著且独立地影响PAD的易感性（P = .02）。在190例无其他动脉粥样硬化病变部位的PAD患者（孤立性PAD）中，观察到ACE D等位基因和-240T等位基因与PAD之间存在显著关联。经Bonferroni校正（P = .02）和心血管危险因素校正后（P = .02），只有ACE D等位基因仍与孤立性PAD相关。ACE基因的单倍型重建分析显示，D/-240T单倍型而非D/-240A单倍型显著影响PAD的易感性（P = .0003）。根据Rutherford分类，未发现所分析的多态性对疾病严重程度有影响。
本研究提供的数据突出了ACE D/-240T单倍型在PAD易感性中的作用，即使在没有其他动脉粥样硬化合并症的情况下也是如此。
