New variants in NLRP3 inflammasome genes increase risk for asthma and Blomia tropicalis-induced allergy in a Brazilian population

Abstract

Atopic asthma is a chronic lung disease of lower airways caused mainly due to action of T-helper (Th) 2 type cytokines, eosinophilic inflammation, mucus hypersecretion and airway remodelling. Interleukin (IL)-33 increases type 2 immunity polarization in airway playing critical role in eosinophilic asthma. On the other hand, NLRP3 inflammasome activation results in the release of caspase-1 (Casp-1) which, in its turn, promotes IL-33 inactivation. Recent studies have shown associations between NLRP3 variants and inflammatory diseases. However, no study with genes in NLRP3 inflammassome route has been conducted so far with asthma and atopy in any population to date. Blood samples were collected from 1246 asthmatic and non-asthmatic children. Associations were tested for single nucleotide polymorphism (SNP)s in NLRP3 and CASP1 with asthma and markers of atopy and in cultures stimulated with Blomia tropicalis (Bt) mite crude extract. The T allele of rs4925648 ( NLRP3) was associated with increased asthma risk (OR 1.50, P = 0.005). In addition, the T allele of rs12130711 polymorphism, whithin the same gene, acted as a protector factor for asthma (OR 0.78, P = 0.038). On the other hand, the C allele of rs4378247 NLRP3 variant was associated with lower levels of IL-13 production when peripheral blood cells were stimulated with Bt (OR 0.39, P = 4E-04). In addition, the greater the number of risk alleles in IL33 / NLRP3 / CASP1 route the greater was the risk for asthma. The T allele of rs7925706 CASP1 variant was also associated with increased risk for asthma (OR 1.47, P = 0.008). In addition, this same allele increased the eosinophil counts in blood (mm3) in asthmatic individuals compared with non-asthmatic (P = 0.0004). These results suggest that NLRP3 and CASP1 polymorphisms may be associated with susceptibility for asthma and markers of atopy in our population.

Inhibition of the Inflammasome Activity of NLRP3 Attenuates HDM-Induced Allergic Asthma

“…Variants in the Nlrp3 gene increase the risk of asthma in patients ( 21 ). The expression of NLRP3 and caspase-1 in BAL fluids from asthmatic patients is higher than that in BAL fluids from healthy controls ( 22 , 23 ).…”

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

“…NLRP3 is located in chromosome region 1q43-q44, with 3 kb upstream of the transcription initiation site (exon and intron) and 2 kb downstream of the termination codon (a total of 37,953 kb) [11]. Recent genetic research has focused on the association between NLRP3 genetic variation and susceptibility to autoimmune and in ammatory diseases [12][13][14][15]. However, they all investigate the polymorphism of the exon and intron genes in the NLRP3 coding region.…”

The effects of NLRP3 and MAVS gene polymorphisms on the risk of asthma: A case–control study

“…In addition, a study found that the C allele of NLRP3 rs4378247 was associated with lower levels of IL-13 production when peripheral blood cells were stimulated with Blomia tropicalis mite crude extract. [ 31 ] In summary, NLRP3 polymorphisms affect the risk of asthma. Notably, a previous study on Helicobacter pylori infection in children showed a significant association between the CC genotype of NLRP3 rs10754558 and eosinophils.…”