The 3’-UTR Polymorphisms in the NLRP3 Gene Associated with the Risk of COPD and Their Putative Effects on the microRNA Mechanism

Abstract

Abstract Objective Evaluating the association between a single nucleotide polymorphism in the 3'UTR region of the miRNAs binding site of the NLRP3 gene and the occurrence and development of Chronic Obstructive Pulmonary Disease (COPD) and providing information to aid in the early detection and treatment of COPD. Methods The regulatory SNPs located in NLRP3 3'UTR region were searched by using dbSNP database and miRNA binding site prediction database. Meanwhile, samples from COPD patients and healthy controls in the same period were used for verification. The clinical baseline information of all subjects was collected, and the transcription level and protein expression level of NLRP3 and the expression level of inflammatory factors downstream of NLRP3 were detected. The effects of SNPs single nucleotide changes on the transcription and expression of inflammatory factors were analyzed. Results The study included 418 participants (249 in the COPD group and 169 in the control group). NLRP3 SNPs with miRNA binding sites include rs10754558 (G>C), rs1664774076 (ATAT>-), and rs1664775106 (C>G). Furthermore, two genotypes, GCG and GCA, were discovered to have a linkage mutation at 3'UTR 459-461. COPD susceptibility is tightly associated to the expression of the rs1664774076 -/- genotype, and the risk of COPD increased by 3.4 times (P≤0.0001). Type 459-461 GCA was substantially related with the likelihood of developing COPD at various stages (P<0.05). Except for rs10754558, all homozygous mutants increased NLRP3 mRNA and protein levels. NLRP3 had the greatest area under the ROC curve for predicting the development and diagnosis of COPD when compared to its downstream inflammatory variables (AUC= 0.9291). Conclusions The NLRP3 rs1664774076 -/- genotype is a COPD susceptibility gene, and the GCA genotype at 459-461 can be used as an early predictor of COPD exacerbation. The NLRP3 3'UTR polymorphism may alter the loss of miRNA binding sites, leading to an increase in NLRP3 expression. In the development of COPD, NLRP3 has a better diagnostic value than traditional inflammatory factors.