The data were normalized using the rank invariant option in the software package BeadStudio

r by altering the availability of transcription factors to the key regulatory elements in the IL4 promoter, thus leading to aspirin hypersensitivity. INTERLEUKIN 13: IL-13 is a key cytokine involved in allergic inflammation by inducing airway eosinophilia and bronchial hyper-reactivity. AIA is characterized by chronic rhinosinusitis and nasal polyposis due to persistent upper and lower airway inflammation with marked eosinophilia. Tight collaboration between pathogen-associated molecular patterns and their receptors initiates an innate immune response, and NLRP3 inflammasomes are activated by pathogen-associated molecular patterns including microbial toxins, live bacteria, and viruses.55 After being activated, NALP3 recruits apoptosis-associated speck-like proteins containing procaspase-1, leading to activation of caspase-1. Activated caspase-1 cleaves the procytokines IL-1b and IL-18 into their active forms. Of 15 tag SNPs of NLRP in a large population, one was significantly associated with AIA. The risk allele of rs4612666 increases the enhancer activity of NLRP3 expression and NLRP3 mRNA stability,56 indicating that the NLRP3 SNP might play an important role in the development of AIA in a gain-of-function manner. Genetic Basis of Aspirin Hypersensitivity Asthma Airway remodeling and fibrosis genes A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 33: ADAM33 is expressed strongly in smooth muscle layers and basement membrane in more than 80% of subjects with asthma but not in normal control subjects, indicating that ADAM33 may be involved in airway remodeling in asthma.57 A genome-wide screen revealed ADAM33 to be a novel asthma-susceptibility gene that plays a role in AHR.58 ADAM33 polymorphisms are associated with asthma susceptibility and airway hyperreactivity in several ethnicities, including the Korean population.59 In a Japanese population, of 10 polymorphic sites, the ST+7, V-1, and V5 sites in the AIA group were significantly different from those in the ATA group. Haplotypes of three sites were significantly different in frequency between the AIA and ATA groups, indicating that the ADAM33 sequence variations are likely to correlate with susceptibility to AIA.60 FIBROUS SHEATH-INTERACTIONG PROTEIN 1: With its primary function in protein binding, the FSIP1 gene is expressed in the airway epithelium. FSIP1 is regulated by amyloid beta precursor protein.61 APP is an integral membrane protein expressed in many tissues, particularly in the synapses of neurons. APP is cleaved by ADAM33. Of 66 PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19805376 SNPs in the FSIP1 gene, one was associated with AIA in a Korean population.62 In Asian populations from the International HapMap Project, the FSIP1 gene is in LD with the thrombospondin-1 gene. The THBS1 gene has been implicated in a network underlying the pulmonary response to oxidative stress in asthma.63 Aspirin leads to a SB-590885 site reduction in THBS1 levels.64 These data suggest that FSIP1 affects aspirin hypersensitivity in asthma associated with the nearby THBS1 gene.ADORA1 SNPs and haplotypes are significantly associated with AIA, suggesting that adenosine might play a crucial role in the development of AIA through interactions with the A and A receptors.73 G PROTEIN-COUPLED RECEPTOR 44: PGD2, a major prostanoid produced by allergen-activated mast cells, is an important mediator in the pathogenesis of eosinophilic airway inflammation via its receptor, a chemoattractant receptor molecule expressed on Th2 cells. The human CRTH2 gene is also expressed in o