Department of Cardiovascular Ultrasound, the First Hospital of China Medical University, Shenyang 110001, China.
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China.
Exp Mol Pathol. 2021 Apr;119:104609. doi: 10.1016/j.yexmp.2021.104609. Epub 2021 Jan 29.
Toll-like receptor 4 (TLR4) is a crucial regulator of inflammatory reactions and vascular remodeling. Elevated TLR4 expression has been proved to be correlated with an increased risk of aortic aneurysm (AA). This study aimed to explore the influence of TLR4 gene polymorphisms on TLR4 expression levels and its probable functional significance in AA disease. A total of 294 AA patients and 285 controls were enrolled in the study and serum TLR4 levels were detected by ELISA. All the participants were genotyped for two tag-SNPs in TLR4 (rs1927914 in the promoter region and rs11536889 in the 3'-untranslated region) using the KASP method. Relative luciferase activity was measured by the dual-luciferase reporter assay system. The rs1927914 TC, TC/CC genotypes and C allele showed associations with increased serum TLR4 levels in the total population and AA patients (all P<0.05). Further stratified analysis demonstrated that AA subjects with TC or TC/CC genotype of rs1927914 had significantly higher serum levels of TLR4 than those with TT genotype in male, age>60y, hypertension, diabetes, TAA type and size>5.0 cm subgroups (all P<0.05). In binary logistic analysis, rs1927914 TC genotype and dominant model presented significant associations with high TLR4 levels (OR = 1.579 and 1.431, P = 0.020 and 0.049, respectively) after adjusting age, hypertension and diabetes. However, rs11536889 polymorphism had no significant influence on serum TLR4 levels. Regarding rs1927914, luciferase activity of the C allele construct was significantly increased in comparison with the T allele construct (0.589 ± 0.004 vs. 0.340 ± 0.014, P<0.001). Our results provided evidence that rs1927914 polymorphism contributed to serum TLR4 levels, possibly by influencing promoter activity of TLR4, and could be a novel genetic factor in the formation of AA.
Toll 样受体 4（TLR4）是炎症反应和血管重塑的关键调节因子。已证明 TLR4 表达升高与腹主动脉瘤（AA）风险增加相关。本研究旨在探讨 TLR4 基因多态性对 TLR4 表达水平的影响及其在 AA 疾病中的可能功能意义。共纳入 294 例 AA 患者和 285 例对照，采用 ELISA 法检测血清 TLR4 水平。采用 KASP 法对 TLR4 （启动子区 rs1927914 和 3'-非翻译区 rs11536889 ）中的两个标签 SNP 进行基因分型。通过双荧光素酶报告基因检测系统测量相对荧光素酶活性。rs1927914TC、TC/CC 基因型和 C 等位基因与总人群和 AA 患者的血清 TLR4 水平升高相关（均 P<0.05）。进一步的分层分析表明，rs1927914TC 或 TC/CC 基因型的 AA 患者，其血清 TLR4 水平明显高于 TT 基因型的男性、年龄>60 岁、高血压、糖尿病、TAA 型和直径>5.0cm 亚组（均 P<0.05）。在二元逻辑分析中，rs1927914TC 基因型和显性模型与高 TLR4 水平显著相关（OR=1.579 和 1.431，P=0.020 和 0.049），调整年龄、高血压和糖尿病后。然而，rs11536889 多态性对血清 TLR4 水平无显著影响。关于 rs1927914，与 T 等位基因构建体相比，C 等位基因构建体的荧光素酶活性显著增加（0.589±0.004 比 0.340±0.014，P<0.001）。我们的结果提供了证据表明 rs1927914 多态性导致血清 TLR4 水平升高，可能通过影响 TLR4 启动子活性，并且可能是 AA 形成的新的遗传因素。
