Reframing paucigranulocytic asthma through genetic endotyping: a hypothesis-generating focus on the 17q21 rs7216389 locus

Purpose of review: Non-T2 asthma is currently defined by missing parameters, such as low blood eosinophils and FeNO, rather than positively identifiable mechanistic features. This definition overlaps with paucigranulocytic asthma (PGA). However, T2-biomarkers fluctuate over time, especially during glucocorticoid therapy, leading to potential over-diagnosis of T2-low asthma. Advancing beyond traditional endotyping is required for precision medicine. Recent findings: Alarmin-driven asthma [interleukin (IL)-33, thymic stromal lymphopoietin (TSLP), IL-25] can drive inflammation even without high T2-markers, but these are difficult to measure clinically. Genetic testing, such as the rs7216389 SNP (17q21 locus, GSDMB/ORMDL3), offers a stable alternative. The T allele is linked to childhood-onset asthma, viral-induced alarmin release, and epithelial dysfunction. Notably, carriers of the T allele are more likely to respond to allergen immunotherapy (AIT). This genetic marker is not subjected to treatment-dependent modification and segregates with both T2-driven and alarmin-driven asthma. Summary: We propose that rs7216389 genotyping could be explored, within a treatable trait framework, to improve the mechanistic characterization of paucigranulocytic or low-biomarker asthma. While current data are associative, this one-time genetic assessment might contribute to research-driven stratification of "hidden" T2- or alarmin-leaning endotypes, potentially guiding the use of AIT and upstream biologics like anti-TSLP.