Genetics of Interleukin 1 Receptor-Like 1 in Immune IL1RL1 IN DISEASE Asthma and other Respiratory Diseases Increased eosinophil count is a phenotype associated with the majority of asthma cases and correlates with severity of the disease as well as response to glucocorticoid treatment [32]. Using asthma mouse models, it was shown that eosino- philic inflammation is significantly decreased following al- lergic stimuli in animals subjected to treatments with recom- binant IL1RL1 or antibodies directed against the membrane- anchored protein [33, 34]. Soluble IL1RL1 has been shown to be sufficient to reduce experimental allergic airway in- flammation using an intravenous IL1RL1 gene transfer mouse model [34], perhaps by acting as a decoy receptor. In addition, a ST2-/- knockdown mouse model of asthma showed decreased airway inflammation [35]. IL1RL1 expression has been shown to increase in murine [35] and human [36] asthmatic lungs; soluble IL1RL1 has been shown to increase in the serum of asthmatic patients during acute attacks, and this increase correlated with lung function decrease as well as an increase in the serum levels of the inflammatory cytokine IL5 [37]. Other in vivo studies of airway allergic inflammation demonstrated a clear in- volvement of soluble IL1RL1 protein in regulating a Th2 response after allergen challenge [35] as well as in the reso- lution of allergen-induced inflammation as assessed by air- way hyper-responsiveness [38]. Since the late 1990s, genetic studies have shown linkage of chromosome 2 with asthma, lung function (as assessed by FEV1%VC, a common clinically-useful index for airflow limitation), eosinophilia and IgE levels [39-41]. Polymorphisms in IL18R1, a gene in tight LD with IL1RL1, were associated with asthma, atopic asthma and airway hyper-responsiveness using a candidate gene ap- proach in a Danish population and the association consis- tently replicated in two other European populations [18]. In the same year, another candidate gene association study documented significant genetic association of the gene clus- ter containing IL1RL1, IL18R1 and IL18RAP with asthma and atopy in a Dutch population [19]. Additional association evidence was reported by the same group using pathway analysis to detect gene-gene interactions in the Toll Like Receptor (TLR)-related pathway. IL1RL1 isoform B has been shown to down-regulate gene expression of TLR4 and TLR1 in vitro after treatment with LPS and in vivo in a LPS- induced shock mouse model [42]. Twenty-nine genes implicated in TLR regulation were selected for a pathway analysis in Dutch populations [43]. IL1RL1 SNPs were associated with allergy and asthma phe- notypes as single SNPs although the significance did not survive multiple testing correction. In addition, when gene x gene interactions were tested using the multifactor dimen- sionality reduction approach, IL1RL1 SNPs were identified as interacting factors in analyses of IgE phenotypes [43]. In a study performed by our group in collaboration with others, we investigated three Canadian and one Australian populations but failed to detect any significant association with IL1RL1 that survived correction for multiple compari- sons [44]. The same cohorts, in addition to one American Current Genomics, 2010, Vol. 11, No. 8 593 population, were used in an association study of genes in the vitamin D pathway with asthma and atopy phenotypes. IL1RL1 SNPs were selected for this study based on the fact that IL1RL1 was shown to be transcriptionally regulated by vitamin D [45]. The genotyping covered more variants of IL1RL1 than the initial study and the number of candidate genes was substantially less (11 versus 120 genes). Signifi- cant associations of these variants were observed with asthma and atopy phenotypes [46]. Given the role of eosinophils in the pathogenesis of asthma, alleles that associate with increased eosinophil count could be detrimental in terms of asthma risk and severity. In a Genome Wide Association Study (GWAS) of eosinophil count in an Icelandic population, a SNP in IL1RL1 (rs1420101) showed the most significant association. The A allele of rs1420101 associated with increased eosinophil count and in further analyses with increased serum IgE as well as with three asthma phenotypes (asthma, atopic asthma, non atopic asthma) in nine European populations and one east Asian population [47]. rs1420101 is an intronic SNP which is in high LD (r2 greater than 80%) with a large number of other variants in IL1RL1, IL18R1 and IL18RAP; this group of SNPs contains mostly intronic SNPs in addition to a coding-synonymous and a few 3’ and 5’ UTR SNPs. No functional studies have been performed thus far to determine the association-causing SNP. It is of note that an association of a SNP in IL33 (rs3939286) with eosinophil count, asthma and atopic asthma was reported in same study, although the IL33 asso- ciation with eosinophil count did not reach genome-wide significance. The same IL33 SNP was associated with nasal polyposis in a Belgian population in a candidate gene study [48]. Wu et al. used GWAS data of childhood asthma in a Mexican population [49] to perform a candidate gene analy- sis. In this study, 237 genes were selected from human and animal model published studies of asthma to have at least one SNP associated with an asthma phenotype. They re- ported IL1RL1 among the most significant associations. Fur- thermore, their results were subjected to multi-marker analy- sis, which confirmed IL1RL1 as a significant finding as well as IL18R1. Collectively, there is strong evidence for genetic associa- tion of IL1RL1 with asthma and related phenotypes. This association is certainly very well supported by the biology of IL1RL1 and related proteins. IL33 is secreted by the airway epithelium in response to stress such as allergens or viruses, and binds to IL1RL1 isoform A on the surface of immune cells. There are excellent reviews about the central role of the epithelium in initiating and sustaining immune responses [50]; IL33/ IL1RL1 isoform A plays a crucial role in that process. The binding of IL1RL1 isoform A and its ligand IL33 triggers the NF B signaling pathway, which leads to the transcription of cytokines needed for a Th2 immune re- sponse. However, the role of IL1RL1 isoform B remains unclear. Several animal models and in vitro studies show that IL1RL1 isoform B prevents the IL33/ IL1RL1 isoform A signaling and consequently attenuates inflammation, indicat-