Strauss Ewa, Waliszewski Krzysztof, Oszkinis Grzegorz, Staniszewski Ryszard
Instytut Genetyki Człowieka Polskiej Akademii Nauk w Poznaniu Zakład Funkcji Kwasów Nukleinowych.
Przegl Lek. 2012;69(10):744-9.
Pathological changes in the vascular vessels, such as the presence of atherosclerotic plaques or aneurysmal dilatations, are associated with the local conditions of ischemial/hypoxia. Polymorphisms in the HIF1A gene, encoding an oxygen-regulated HIF-1 subunit (HIF-1a), determine inter-individual variability in vascular response to hypoxia. Stimulation of selected pathways, related to this response (i.e. angiogenesis) is impaired by cigarette smoke exposure. In this work, we examined the associations between 1772C>T polymorphism (rs11549465) located in the coding region of HIF1A gene (Pro582-Ser), smoking and the occurrence of abdominal aortic aneurysm (AAA). Moreover, the relations of these factors with the presence of peripheral arterial disease (PAD) in patients with AAA were studied. The case-control study was designed, in which a group of 1060 Caucasian subjects: 535 AAA patients and 525 controls, was analyzed. Data regarding smoking status were collected using questionnaire. Past and current smokers were analyzed together. In the group of 220 AAA subjects the coexistence of PAD was characterized. HIF-1A genotypes were assessed by PCR-RFLP method. Genetic-environmental interactions were examined by a two-by-four tables. In these analyzes, logistic regression models were used to adjusting for the relevant covariates. The frequency of HIF1A 1772T allele in AAA group (0,067) was similar to that observed in the control group (0,070). In the analyses of genetic-environmental interactions was observed that the co-occurrence of HIF1A 1772CT and TT genotypes and exposure to tobacco smoke has a strong multiplicative effect on the susceptibility to the AAA development. The age and gender adjusted odds ratios (ORs) were: 7,6 for smoking alone (p<0,0001); 0,65 for 1772CT and TT genotypes alone (p=0,3) and 14,4for smoking plus 1772CT and TT genotypes (p<0,0001). The proportion of smokers carrying 1772T allele was higher among patients with advanced form of PAD (femoro-popliteal or aorto-iliac occlusion, 18%) as compared to the frequency in the rest of AAA patients (9,3%, p=0,05). In a multivariate analysis smoking in combination with the HIF1A 1772T allele occurrence was the strongest independent predictor of AAA (OR=14,5; p<0,0001). In conclusion, HIF1A 1772T allele enhances theAAA risk determined by smoking and promotes the development of a more complex phenotype of the disease in smokers (with coexisting severe peripheral arterial disease).
血管的病理变化，如动脉粥样硬化斑块或动脉瘤样扩张的存在，与局部缺血/缺氧状况相关。编码氧调节的HIF-1亚基（HIF-1α）的HIF1A基因中的多态性决定了个体间血管对缺氧反应的变异性。与这种反应（即血管生成）相关的特定途径的刺激会因接触香烟烟雾而受损。在这项研究中，我们研究了位于HIF1A基因编码区（Pro582-Ser）的1772C>T多态性（rs11549465）、吸烟与腹主动脉瘤（AAA）发生之间的关联。此外，还研究了这些因素与AAA患者外周动脉疾病（PAD）存在情况的关系。设计了病例对照研究，分析了一组1060名白种人受试者：535例AAA患者和525例对照。使用问卷收集有关吸烟状况的数据。将过去和现在的吸烟者一起分析。在220例AAA受试者组中，对PAD的共存情况进行了特征描述。通过PCR-RFLP方法评估HIF-1A基因型。通过二乘四表检验基因-环境相互作用。在这些分析中，使用逻辑回归模型对相关协变量进行调整。AAA组中HIF1A 1772T等位基因的频率（0.067）与对照组中观察到的频率（0.070）相似。在基因-环境相互作用分析中观察到，HIF1A 1772CT和TT基因型与接触烟草烟雾的共同出现对AAA发生的易感性具有强烈的相乘效应。年龄和性别调整后的优势比（OR）分别为：单独吸烟为7.6（p<0.0001）；单独1772CT和TT基因型为0.65（p=0.3）；吸烟加1772CT和TT基因型为14.4（p<0.0001）。与其余AAA患者的频率（9.3%，p=0.05）相比，在晚期PAD（股腘或主髂动脉闭塞）患者中携带1772T等位基因的吸烟者比例更高。在多变量分析中，吸烟与HIF1A 1772T等位基因的出现相结合是AAA最强的独立预测因素（OR=14.5；p<0.0001）。总之，HIF1A 1772T等位基因增加了由吸烟决定的AAA风险，并促进了吸烟者中更复杂疾病表型的发展（伴有严重外周动脉疾病共存）。
