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

TY - JOUR

T1 - Reframing paucigranulocytic asthma through genetic endotyping

T2 - a hypothesis-generating focus on the 17q21 rs7216389 locus

AU - Poto, Remo

AU - Chan, Rory

AU - Breda, Daniela

AU - Varricchi, Gilda

AU - Burastero, Samuele E.

N1 - Publisher Copyright: Copyright © 2026 The Author(s). Published by Wolters Kluwer Health, Inc.

PY - 2026/3/24

Y1 - 2026/3/24

N2 - 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.

AB - 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.

KW - alarmins

KW - rs7216389

KW - severe asthma

KW - thymic stromal lymphopoietin

KW - type 2 inflammation

UR - https://www.scopus.com/pages/publications/105037590932

U2 - 10.1097/ACI.0000000000001145

DO - 10.1097/ACI.0000000000001145

M3 - Article

C2 - 41885394

AN - SCOPUS:105037590932

SN - 1528-4050

JO - Current Opinion in Allergy and Clinical Immunology

JF - Current Opinion in Allergy and Clinical Immunology

ER -