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

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.