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Functional SNP in the 3’UTR of PON1 is Associated with the Risk of Calcific Aortic Valve Stenosis via MiR-616

机译:PON1 3’UTR中的功能性SNP与通过MiR-616发生钙化主动脉瓣狭窄的风险有关

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Background/Aims Previous studies have examined the associations between the single nucleotide polymorphism in the Paraoxonase 1 (PON1) gene and development of calcific aortic valve stenosis (CAVS). The association between functional SNP in 3’UTR of PON1 and the risk of CAVS, however, is unclear. In this study, we investigated the role of SNP in the regulation of PON1 expression via miR-616, as well as the association of SNP with the risk of CAVS. Methods Two hundred and sixteen patients with CAVS and 243 CAVS-free participants were recruited in this study.They all obtained transthoracic echocardiogram and the ejection fraction (EF) and aortic valve area were recorded and analyzed. The PON1 expression were measured by western blot, Quantitative Real-Time Polymerase Chain Reaction were used to examine the transcriptional activity of miR-616 and PON1. Differences between CVAS patients and controls in terms of genotype frequency distribution and the estimates of Hardy-Weinberg equilibrium were evaluated using chi-square tests. Logistic regression modeling was used to determine the association between the independent effect of rs3735590 SNP and the interaction between genotype, PON1 activity, and other covariates on lipids and CAVS risk. All statistical analyses were performed using SPSS, version 17.0.1 for Windows (SPSS Inc., Chicago, IL). A p value of < 0 .05 was considered significant for all analyses. Results This study confirmed that PON1 is a validated target gene of miR-616 in liver cells. The relative quantification representing the expression of PON1 mRNA and the serum level of PON1 protein was decreased in the TT genotype. Moreover, the expression of PON1 had a negative regulatory relationship with the expression of miR-616(r=-0.3959, P<0.05) in human tissues. The patients with CT OR TT genotype at loci rs3735590 had a lower risk of CAVS than patients with the CC genotype. Conclusions Our results suggest that functional SNP in the 3’UTR of PON1 regulates the expression of PON1 via miR-616, and such SNP is associated with the risk of CAVS in human.
机译:背景/目的先前的研究已经检查了对氧磷酶1(PON1)基因中的单核苷酸多态性与钙化主动脉瓣狭窄(CAVS)的发展之间的关联。 PON1 3’UTR中功能性SNP与CAVS风险之间的关联尚不清楚。在这项研究中,我们调查了SNP在通过miR-616调节PON1表达中的作用,以及SNP与CAVS风险的关系。方法招募116例CAVS患者和243例无CAVS患者,均获得经胸超声心动图,记录并分析射血分数(EF)和主动脉瓣面积。用western blot检测PON1的表达,实时定量聚合酶链反应(RTS)检测miR-616和PON1的转录活性。使用卡方检验评估CVAS患者和对照组之间在基因型频率分布和Hardy-Weinberg平衡估计方面的差异。使用逻辑回归模型确定rs3735590 SNP的独立作用与基因型,PON1活性以及脂质和CAVS风险的其他协变量之间的相互作用。使用Windows(SPSS Inc.,Chicago,IL)版本17.0.1的SPSS进行所有统计分析。 p值为<所有分析均将0 .05视为有意义。结果这项研究证实PON1是肝细胞中miR-616的有效靶基因。在TT基因型中,代表PON1 mRNA表达和PON1蛋白血清水平的相对定量降低了。此外,PON1的表达与人体组织中的miR-616的表达负相关(r = -0.3959,P< 0.05)。 rs3735590位点的CT OR TT基因型患者的CAVS风险低于CC基因型患者。结论我们的结果表明PON1的3'UTR中的功能性SNP通过miR-616调节PON1的表达,并且这种SNP与人类CAVS的风险有关。

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