背景:尽管晚期糖基化终产物受体(RAGE)在冠状动脉疾病中的意义已有报道,其在冠状动脉扩张症(CAE)中的作用尚未确定。此外,在可溶性RAGE(sRAGE)水平的范围内,RAGE多态性的影响尚未明确。因此,我们旨在研究RAGE-374T>A(rs1800624)和G82S(rs2070600)的功能多态性在CAE发育中的影响。
方法:这项前瞻性观察研究是在2组患者中进行的,这些患者接受了选择性冠状动脉造影(CAG),以在无创性心脏试验阳性后进行评估。第一组包括98例非阻塞性冠状动脉疾病和CAE患者,II组(对照组)包括100例冠状动脉正常的患者。使用Taqman®基因分型测定通过实时PCR对SNP进行基因分型。通过ELISA测定血清sRAGE和可溶性凝集素样氧化受体1(sOLR1),并酶促测定血清脂质。
结果:CAE患者中RAGE-374A等位基因和-374AA基因型的频率明显高于对照组(p<0.001)。SRAGE水平在研究组之间没有差异,而CAE中sOLR1水平升高(p=0.004)。在没有全身性疾病的对照组中,-374A等位基因与低sRAGE水平相关(p<0.05),但这种关联在HT对照组中并不显著.同样,同时患有HT和T2DM的CAE患者的sRAGE水平高于无全身性疾病的患者(p=0.02)。在CAE组的总分析和亚组分析中,-374A等位基因也与较年轻的患者年龄和较高的血小板计数相关。在相关性分析中,在所有这些CAE组中,-374A等位基因也与年龄呈负相关,与Plt呈正相关。在总CAE组中,sRAGE水平与年龄呈正相关,与HDL-胆固醇水平呈负相关。另一方面,在总数中,sRAGE和Plt之间呈负相关,高血压和无全身性疾病控制亚组。多因素logistic回归分析证实-374A等位基因(p<0.001),高脂血症(p<0.05),高sOLR1水平(p<0.05)是CAE的危险因素。ROC曲线分析表明,RAGE-374A等位基因的AUC为0.713(灵敏度:83.7%,特异性:59.0%),高于HLD(灵敏度:59.2%,特异性:69.0%),HT(灵敏度:62.4%,特异性:61.1%)和高sOLR1水平(≥0.67ng/ml))(灵敏度:59.8%,特异性:58.5%)。
结论:除了首次证明-374A等位基因与CAE风险增加之间的关系外,我们的结果表明,CAE患者的抗高血压和抗糖尿病治疗会导致sRAGE水平升高.总CAE组中预期的-374A等位基因和低sRAGE水平之间缺乏关联归因于高血压患者比例高,因此归因于抗高血压治疗。此外,RAGE-374A等位基因与CAE和Plt较高的年龄有关,提示-374A也可能与血小板活化有关,在CAE的发病机制中发挥作用。然而,我们的数据需要在一项大型研究中得到证实才能得出明确的结论.
BACKGROUND: Although the implication of receptor of advanced glycation endproducts (RAGE) has been reported in coronary artery disease, its roles in coronary artery ectasia (CAE) have remained undetermined. Furthermore, the effect of RAGE polymorfisms were not well-defined in scope of soluble RAGE (sRAGE) levels. Thus, we aimed to investigate the influence of the functional polymorphisms of RAGE -374T > A (rs1800624) and G82S (rs2070600) in CAE development.
METHODS: This prospective observational study was conducted in 2 groups selected of 2452 patients who underwent elective coronary angiography (CAG) for evaluation after positive noninvasive heart tests. Group-I included 98 patients with non-obstructive coronary artery disease and CAE, and Group-II (control) included 100 patients with normal coronary arteries. SNPs were genotyped by real-time PCR using Taqman® genotyping assay. Serum sRAGE and soluble lectin-like oxidized receptor-1 (sOLR1) were assayed by ELISA and serum lipids were measured enzymatically.
RESULTS: The frequencies of the RAGE -374A allele and -374AA genotype were significantly higher in CAE patients compared to controls (p < 0.001). sRAGE levels were not different between study groups, while sOLR1 levels were elevated in CAE (p = 0.004). In controls without systemic disease, -374A allele was associated with low sRAGE levels (p < 0.05), but this association was not significant in controls with HT. Similarly, sRAGE levels of CAE patients with both HT and T2DM were higher than those no systemic disease (p = 0.02). The -374A allele was also associated with younger patient age and higher platelet count in the CAE group in both total and subgroup analyses. In the correlation analyses, the -374A allele was also negatively correlated with age and positively correlated with Plt in all of these CAE groups. In the total CAE group, sRAGE levels also showed a positive correlation with age and a negative correlation with HDL-cholesterol levels. On the other hand, a negative correlation was observed between sRAGE and Plt in the total, hypertensive and no systemic disease control subgroups. Multivariate logistic regression analysis confirmed that the -374A allele (p < 0.001), hyperlipidemia (p < 0.05), and high sOLR1 level (p < 0.05) are risk factors for CAE. ROC curve analysis shows that RAGE -374A allele has AUC of 0.713 (sensitivity: 83.7 %, specificity: 59.0 %), which is higher than HLD (sensitivity: 59.2 %, specificity: 69.0 %), HT (sensitivity: 62.4 %, specificity: 61.1 %) and high sOLR1 level (≥0.67 ng/ml)) (sensitivity: 59.8 %, specificity: 58.5 %).
CONCLUSIONS: Beside the demonstration of the relationship between -374A allele and increased risk of CAE for the first time, our results indicate that antihypertensive and antidiabetic treatment in CAE patients causes an increase in sRAGE levels. The lack of an association between the expected -374A allele and low sRAGE levels in total CAE group was attributed to the high proportion of hypertensive patients and hence to antihypertensive treatment. Moreover, the RAGE -374A allele is associated with younger age at CAE and higher Plt, suggesting that -374A may also be associated with platelet activation, which plays a role in the pathogenesis of CAE. However, our data need to be confirmed in a large study for definitive conclusions.