Independent association of a 17q21 variant with exacerbations in type 2–low adult asthma

Background: The genetic factors contributing to exacerbations in type 2–low asthma are not well understood. Objective: We sought to clarify the association between variants in gasdermin B/orosomucoid-like 3 (GSDMB/ORMDL3) on 17q21 and exacerbations in type 2–low asthma. Methods: This follow-up study of the multicenter Kinki Hokuriku Airway disease Conference (KiHAC) enrolled adults with asthma who were receiving inhaled corticosteroids. It examined associations between asthma exacerbations requiring systemic corticosteroids over 2 years and clinical and genetic factors in patients with the type 2–low endo-genotype, defined by serum periostin levels lower than 95 ng/mL and the IL4RA rs8832 A allele. Exacerbation risks were also evaluated in patients with the type 2–low genotype, defined by both the POSTN rs3829365 C allele and the IL4RA rs8832 A allele, using the KiHAC and replication cohorts. The genetic variant rs7216389 in GSDMB was the primary focus for assessing genetic risk. Results: A total of 115 patients with the type 2–low endo-genotype were analyzed (mean age, 62 years; 76.5% female). During the 2-year follow-up, 32 patients experienced 1 or more exacerbation. Multivariate analysis identified the rs7216389 TT genotype, recent exacerbations, female sex, and higher body mass index as independent risk factors for asthma exacerbations in patients with the type 2–low endo-genotype. The association between the rs7216389 TT genotype and exacerbations was confirmed in patients with the type 2–low genotype in the KiHAC (n = 89) and replication (n = 125) cohorts. Conclusions: The rs7216389 TT variant on 17q21 may be an independent risk factor for exacerbations in adults with type 2–low asthma, highlighting the role of GSDMB in its pathophysiology.