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IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type‐2 inflammatory endotype
Author(s) -
Sunadome H.,
Matsumoto H.,
Petrova G.,
Kanemitsu Y.,
Tohda Y.,
Horiguchi T.,
Kita H.,
Kuwabara K.,
Tomii K.,
Otsuka K.,
Fujimura M.,
Ohkura N.,
Tomita K.,
Yokoyama A.,
Ohnishi H.,
Nakano Y.,
Oguma T.,
Hozawa S.,
Nagasaki T.,
Ito I.,
Oguma T.,
Inoue H.,
Tajiri T.,
Iwata T.,
Izuhara Y.,
Ono J.,
Ohta S.,
Hirota T.,
Tamari M.,
Yokoyama T.,
Niimi A.,
Izuhara K.,
Mishima M.
Publication year - 2017
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.12927
Subject(s) - endotype , medicine , odds ratio , asthma , genotype , periostin , exacerbation , confidence interval , immunology , gastroenterology , biology , genetics , extracellular matrix , gene
Summary Background Genetic markers of susceptibility to asthma exacerbations in adults remain unclear. Objective To identify genetic markers of asthma exacerbations, particularly in patients with type‐2 inflammatory endotype. Methods In this observational study of patients enrolled in the Kinki Hokuriku Airway disease Conference multicenter study, frequency of exacerbations requiring systemic corticosteroids during 2 years after enrolment and associated risk factors was determined. For genetic marker analysis, interleukin‐4 receptor α ( IL 4 RA ) rs8832 and a disintegrin and metalloprotease 33 ( ADAM 33 ) S_2 (rs528557), T_1 (rs2280091), T_2 (rs2280090), and V_4 (rs2787094) variants were included. Elevated serum periostin levels at enrolment (≥95 ng/ mL , defined as type‐2 inflammatory endotype) were considered in the analysis. Results Among 217 patients who were successfully followed up for 2 years after enrolment, 60 patients showed at least one asthma exacerbation during the 2 years. Airflow limitation (% FEV 1 <80%) and recent exacerbations but not genetic variants were identified as risk markers of exacerbations. A total of 27 patients showed type‐2 inflammatory endotype (serum periostin ≥95 ng/ mL at enrolment) and subsequent exacerbations; risk factors in these patients were airflow limitation (odds ratio, 6.51; 95% confidence interval (CI): 2.37–18.6; P =.0003), GG genotype of IL 4 RA rs8832 (odds ratio, 4.01; 95% CI: 1.47–11.0; P =.007), and A allele of ADAM 33 T_2 (odds ratio, 2.81; 95% CI: 1.05–7.67; P =.04) by multivariate analysis. In addition, GG genotype of IL 4 RA rs8832 was associated with type‐2 endotype, whereas A allele of ADAM 33 T_2 was associated with mixed type of eosinophilic/type‐2 and neutrophilic inflammations. Conclusions and Clinical Relevance IL 4 RA and ADAM 33 variants may be risk markers of asthma exacerbations in type‐2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.