Functional analysis of protective IL1RL1 variants associated with asthma risk

Genome-wide association studies (GWASs) have identified polymorphisms in both IL33 and IL1RL1, the gene encoding ST2, the high-affinity chain of the IL-33 receptor, that associate with asthma susceptibility.1 Furthermore, environmental agents can trigger IL-33 bioavailability, which in turn promotes proinflammatory type 2 responses through the ST2-IL-33 complex.2 Immune responses to helminth infections and allergic challenges are compromised in Il33-/- or Il1rl1-/- mice, highlighting the significance of this pathway in both protective and pathologic states.2 Likewise, increased IL-33 levels have been detected in patients with asthma, allergic rhinitis, and other atopic diseases. Asthma cases included 522 samples of European ancestry from the Genentech clinical trials BOBCAT, EXTRA, MILLY, and MOLLY compared with 4465 population control subjects of European ancestry from the Cancer Genetic Markers of Susceptibility (CGEMS) GWAS.4-7 Interestingly, these same polymorphisms were also found to be associated with the risk to cardiovascular disease and increased soluble ST2 and IL-33 levels.8 As in the study by Moffatt et al3 and others,1 we find these SNPs to be protective against asthma risk in our study population (rs3771166: P = 3.4 x 10-4; odds ratio, 0.77; Table I; for simplicity, we refer to this as the protective IL1RL1 haplotype in contrast to the common haplotype).