IL1RL1 gene variations are associated with asthma exacerbations in children and adolescents using inhaled corticosteroids

To the editor, Asthma, one of the most common chronic diseases in childhood, is caused by interactions between genes and environmental factors. The mainstay of treatment is daily use of inhaled corticosteroids (ICS), which are the most effective medication for controlling asthma symptoms and preventing (severe) exacerbations. ICS use reduces both hospitalizations and mortality rates1 and improves asthma con‐ trol; reflected in forced expiratory volume in 1 second (FEV1) levels and fraction of exhaled nitric oxide (FeNO). These effects are par‐ ticularly observed in asthma patients with eosinophilic, type 2 air‐ way inflammation.2 However, responses to ICS are heterogeneous, which while controversial, possibly reflect genetic associations.3,4 Genome‐wide association studies (GWAS) have reproducibly found the Interleukin 1 receptor like 1 (IL1RL1, ST2) gene to be associ‐ ated with asthma susceptibility.5 IL1RL1 single‐nucleotide polymor‐ phisms (SNPs) and IL1RL1 expression levels have been associated with blood eosinophils and markers of Th2 type inflammation.6,7 However, the influence of IL1RL1 SNPs on the effectiveness of asthma treatment has not been investigated. Since the IL‐33/IL1RL1 pathway has been associated with eosinophilic, type 2, inflamma‐ tion, we hypothesized that IL1RL1 SNPs may affect corticosteroid treatment response in asthma patients. Since IL1RL1‐a functions as a decoy receptor to dampen IL‐33‐induced signaling, genetically de‐ termined low levels of IL1RL1‐a may predispose to enhanced IL‐33‐ induced inflammation with consequently more exacerbations. In the current study, we investigated whether IL1RL1 gene vari‐ ants are associated with asthma exacerbations (based on ER visits/ hospitalizations and courses of oral corticosteroid [OCS] use), ques‐ tionnaire‐based asthma control and FeNO levels in asthma patients using ICS. Furthermore, we aimed to identify whether there is a pharmacogenetic effect of IL1RL1 variants on change in FeNO lev‐ els and FEV1% predicted in asthma patients after 4‐6 weeks of ICS treatment. After close inspection of the Linkage Disequilibrium struc‐ ture of IL1RL1, we selected 6 IL1RL1 SNPs that tag important LD blocks in IL1RL1 (r2 > .8) with SNPs previously found to be associ‐ ated with asthma5; rs13431828, rs1041973, rs1420101, rs1946131, rs1921622, and rs10204137 (Table S1). Cross‐sectional IL1RL1 SNP discovery analysis was performed in ICS treated asthmatic children, mainly of European ancestry, from the Pharmacogenetics of Asthma Medication in Children: Medication with Anti‐inflammatory effects (PACMAN) cohort (N = 820) using logistic and linear regression mod‐ els. We replicated FDR corrected significant findings (P < .05) in four different cohorts collaborating within the Pharmacogenomics in Childhood Asthma (PiCA) consortium,8 one Hispanic/Latino study; Genes‐Environment and Admixture in Latino Americans (GALA II, N = 876) study, one African American population; Study of African Americans, Asthma, Genes, and Environments (SAGE, N = 525), and two European studies (≥96% European ancestry); the Effectiveness and Safety of Treatment with Asthma Therapy in children (ESTATe, N = 197) and SLOVENIA (N = 104). In addition, we performed a me‐ ta‐analysis (N = 2412). The longitudinal effect of IL1RL1 on FeNO lev‐ els and FEV1% predicted upon ICS treatment in asthmatic children and adults was assessed in the SLOVENIA cohort. Conditional analy‐ sis was performed in PACMAN to assess the independent effects of the IL1RL1 SNPs. A detailed representation of the included cohorts and the allele frequencies of the IL1RL1 SNPs are provided in Tables S2 and S3, respectively. In PACMAN, we found a significant association be‐ tween four of the six SNPs (rs13431828, rs1420101, rs1921622, and rs10204137) with ER visits and “any exacerbation” (Table 1A‐C), which were selected for the replication study. Sensitivity analyses on Dutch ethnicity, atopy, and medication adherence did not change these results. We did not observe an association with question‐ naire‐based asthma control or FeNO measurements (Table S4A‐B). In GALA II, we replicated our findings with significant results with the same direction of effect for rs13431828, rs1420101, and rs1921622 on ER visits/hospitalizations and “any exacerbation.” Rs10204137 showed a significant association with “any exacerba‐ tion” (Table 1A‐C). In SAGE, rs1921622 was associated with “any exacerbation” but the direction of the effect differed when com‐ pared to PACMAN. No association between IL1RL1 and question‐ naire‐based asthma control was found. In the smaller SLOVENIA and ESTATe studies, no significant cross‐sectional or longitudinal associ‐ ations were found (Table S5). Meta‐analysis of the 4 IL1RL1 SNPs carried through to replication showed statistically significant results for rs13431828. The C allele of rs13431828 was associated with ER visits/hospitalizations (OR = 1.32, P = .02) and increased risk of “any exacerbations” (1.31, P = .02; Table 1A‐ C, Figure 1). No evidence of heterogeneity was found (Q = 3.6, P = .33). Conditional analysis in PACMAN on rs13431828, rs142010, rs1921622, and rs10204137 for “any exacerbation” indicated