Strauss Ewa, Waliszewski Krzysztof, Oszkinis Grzegorz, Staniszewski Ryszard
Institute of Human Genetics of the Polish Academy of Sciences, Poznan, Poland.
Department of General and Vascular Surgery, Poznan University of Medical Sciences, Poznan, Poland.
J Vasc Surg. 2015 May;61(5):1105-13.e3. doi: 10.1016/j.jvs.2014.02.007. Epub 2014 Mar 20.
The pathogenesis of aortic diseases, both aneurysmal and occlusive, is associated with the occurrence of local ischemic/hypoxic conditions, but the genetic factors that differentiate the predisposition to specific types of aortic diseases are largely unknown. In this study, the functional variants in genes involved in the hypoxia signaling pathway, hypoxia-inducible factor-1α (HIF1A) 1772C>T, 1790G>A, and vascular endothelial growth factor (VEGFA) -634G>C, were analyzed in search of the associations specific to abdominal aortic aneurysm (AAA) development.
The study encompassed a series of 518 patients with AAA, 354 patients with aortoiliac occlusive disease, and 541 controls. In AAA patients, the occurrence of peripheral arterial disease (PAD) was examined with duplex arterial scanning. Genotypes were determined by the polymerase chain reaction/restriction fragment length polymorphism method or with TaqMan probes.
In univariate analysis, a significantly increased risk for development of AAA without coexisting PAD was found in VEGFA -634C allele carriers (effect of allele dose: odds ratio [OR], 1.38; P = .012). In VEGFA -634CC homozygotes, the risk was enhanced by the interaction with HIF1A 1772CC-1790GG genotype (OR, 2.41; P = .008). This joint effect of homozygous genotypes also influenced the AAA risk independently of PAD coexistence (OR, 1.87; P = .036). In contrast, the minor allele of the HIF1A 1772C>T polymorphism (1772T and 1772T-1790G haplotype) was significantly associated with the occurrence of AAA with concomitant PAD (OR, 2.02; P = .009 for the dominant model). This effect was enhanced in the VEGF -634GG homozygotes (OR, 2.86; P = .005) and among smokers (OR, 3.10; P = .001). The individual effects of the HIF1A 1772 and VEGFA -634 polymorphisms on AAA risk remained significant in multivariable analysis after adjustment for the traditional vascular risk factors and analyzed polymorphisms. None of the studied variants influenced the risk of aortoiliac occlusive disease.
This study identifies polymorphisms in the HIF1A and VEGF genes as potential genetic markers that indicate the predisposition to either AAA coexisting with peripheral atherosclerosis or AAA without such lesions, suggesting the genetic heterogeneity of this disease. The HIF1A 1772T allele also seems to be a genetic risk factor that determines sensitivity to cigarette smoke exposure. Further work is needed to confirm the findings in an independent samples set and to study the functional role of studied variants in AAA.
主动脉疾病（包括动脉瘤性和闭塞性）的发病机制与局部缺血/缺氧状态的发生有关，但区分特定类型主动脉疾病易感性的遗传因素在很大程度上尚不清楚。在本研究中，对缺氧信号通路相关基因（缺氧诱导因子-1α（HIF1A）1772C>T、1790G>A以及血管内皮生长因子（VEGFA）-634G>C）中的功能性变异进行了分析，以寻找与腹主动脉瘤（AAA）发生相关的特异性关联。
该研究纳入了518例AAA患者、354例主髂动脉闭塞性疾病患者以及541例对照。在AAA患者中，采用双功动脉扫描检查外周动脉疾病（PAD）的发生情况。通过聚合酶链反应/限制性片段长度多态性方法或TaqMan探针确定基因型。
在单因素分析中，发现VEGFA -634C等位基因携带者发生无并存PAD的AAA的风险显著增加（等位基因剂量效应：比值比[OR]，1.38；P = 0.012）。在VEGFA -634CC纯合子中，与HIF1A 1772CC-1790GG基因型的相互作用增强了风险（OR，2.41；P = 0.008）。纯合基因型的这种联合效应也独立于PAD并存影响AAA风险（OR，1.87；P = 0.036）。相比之下，HIF1A 1772C>T多态性的次要等位基因（1772T以及1772T-1790G单倍型）与并存PAD的AAA的发生显著相关（显性模型的OR，2.02；P = 0.009）。在VEGF -634GG纯合子中（OR，2.86；P = 0.005）以及吸烟者中（OR，3.10；P = 0.001）这种效应增强。在对传统血管危险因素和分析的多态性进行校正后的多变量分析中，HIF1A 1772和VEGFA -634多态性对AAA风险的个体效应仍然显著。所研究的变异均未影响主髂动脉闭塞性疾病的风险。
本研究确定HIF1A和VEGF基因中的多态性为潜在的遗传标志物，表明易患与外周动脉粥样硬化并存的AAA或无此类病变的AAA，提示该疾病的遗传异质性。HIF1A 1772T等位基因似乎也是决定对香烟烟雾暴露敏感性的遗传危险因素。需要进一步的工作来在独立样本集中证实这些发现，并研究所研究变异在AAA中的功能作用。
