Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey; Department of Medical Biochemistry, Faculty of Medicine, Istanbul Nisantasi University, Istanbul, Turkey.
Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey; Department of Medical Biology, Bezmialem Vakıf University, Istanbul, Turkey.
Gene. 2024 Jul 20;916:148450. doi: 10.1016/j.gene.2024.148450. Epub 2024 Apr 7.
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.
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.
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 %).
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.
虽然受体的晚期糖基化终产物（RAGE）的含义已在冠状动脉疾病中报道，但其在冠状动脉扩张（CAE）中的作用仍未确定。此外，RAGE 多态性对可溶性 RAGE（sRAGE）水平的影响范围尚不清楚。因此，我们旨在研究 RAGE -374T> A（rs1800624）和 G82S（rs2070600）的功能多态性对 CAE 发展的影响。
本前瞻性观察研究纳入了 2452 名因无创性心脏试验阳性而行选择性冠状动脉造影（CAG）评估的患者，分为两组。组 I 包括 98 例非阻塞性冠状动脉疾病合并 CAE 患者，组 II（对照组）包括 100 例冠状动脉正常的患者。采用 Taqman®基因分型检测试剂盒，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型受体-1（sOLR1），采用酶法测定血清脂质。
与对照组相比，CAE 患者的 RAGE -374A 等位基因和 -374AA 基因型的频率明显更高（p<0.001）。研究组之间的 sRAGE 水平没有差异，而 CAE 患者的 sOLR1 水平升高（p=0.004）。在没有系统性疾病的对照组中，-374A 等位基因与低 sRAGE 水平相关（p<0.05），但在 HT 对照组中这种相关性不显著。同样，HT 和 T2DM 合并 CAE 患者的 sRAGE 水平高于无系统性疾病患者（p=0.02）。-374A 等位基因也与 CAE 组中年轻患者年龄和血小板计数较高相关，在总组和亚组分析中均如此。在相关性分析中，-374A 等位基因也与所有这些 CAE 组中的年龄呈负相关，与血小板呈正相关。在总 CAE 组中，sRAGE 水平也与年龄呈正相关，与高密度脂蛋白胆固醇水平呈负相关。另一方面，在总、高血压和无系统性疾病对照组中，sRAGE 与血小板呈负相关。多变量 logistic 回归分析证实，-374A 等位基因（p<0.001）、高脂血症（p<0.05）和高 sOLR1 水平（p<0.05）是 CAE 的危险因素。ROC 曲线分析显示，RAGE -374A 等位基因的 AUC 为 0.713（敏感性：83.7%，特异性：59.0%），高于 HLD（敏感性：59.2%，特异性：69.0%）、HT（敏感性：62.4%，特异性：61.1%）和高 sOLR1 水平（≥0.67ng/ml）（敏感性：59.8%，特异性：58.5%）。
除了首次证明 -374A 等位基因与 CAE 风险增加之间的关系外，我们的结果还表明，CAE 患者的降压和降糖治疗会导致 sRAGE 水平升高。在总 CAE 组中，预期的 -374A 等位基因与低 sRAGE 水平之间没有关联，这归因于高血压患者的比例较高，因此需要进行降压治疗。此外，RAGE -374A 等位基因与 CAE 的年轻发病年龄和较高的血小板计数相关，提示 -374A 可能也与血小板激活有关，而血小板激活在 CAE 的发病机制中起作用。然而，我们的数据需要在一项大规模研究中得到证实，以得出明确的结论。
