A meta-analysis of four studies identified three new genes associated with allergic asthma

Associations between Interleukin 6 (IL-6), a key cytokine in inflammation, and asthma were reported, with results varying across phenotypes. We aimed to identify new asthma-associated genes involved with IL6 in inflammation-related pathways while accounting for phenotypic heterogeneity of asthma according to allergic status and age of onset. This pathway-based strategy identifying 1,323 IL6-related genes was applied among 3,435 European-ancestry participants (mean age: 31 years, 54% women, 44% asthma, 44% allergy, 26% adult-onset asthma) from four independent epidemiological studies: EGEA, FEAS, and ALSPAC (discovery samples), and SLSJ (replication sample). Associations between all SNPs within these genes and asthma phenotypes were estimated by logistic models in each study, followed by meta-analyses across studies, and conducted separately for childhood-onset and adult-onset asthma. Two SNPs were specifically associated with adult-onset allergic asthma, located in PTPRE (p-meta=3x10-6) and in FZD7 (p-meta=1.7x10-4). Two other SNPs were specifically associated with childhood-onset allergic asthma, located in IL33 (p-meta=2.5x10-7), and in SASH1 (p-meta=1.1x10-4). The SNPs located in PTPRE and IL33 reached the significance level of association. Applying this approach and accounting for the phenotypic heterogeneity of asthma, we identified three new genes PTPRE, FZD7 and SASH1 associated with asthma, and not detected before by classical approach of GWAS. They play a crucial role in key biological processes involved in asthma development, suggesting potential new targets for asthma prevention.